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Directorate-General for Health and Food Safety
SCIENTIFIC COMMITTEE ON
TOXICITY, ECOTOXICITY AND THE
ENVIRONMENT (CSTEE)
Terms of reference
A. On the basis of the Communication from the Government of the Federal Republic of Germany to the European Commission of 11 December 1998 (heretofore indicated as "German communication"), justifying the reasons why the German Government intends to incorporate national provisions that divert from Directive 97/69/EC which contains, among others, the classification and labelling of mineral wool, the CSTEE is hereby asked whether the answers contained in the document "Technical Report on the reasons put forward by the Federal Republic of Germany for applying national provisions which divert from the requirements of Directive 97/69EC, the 23rd Adaptation to technical progress of Council Directive 67/548 EEC (heretofore indicated as "Technical Report") correctly address the arguments put forward in the German Communication. The CSTEE is invited to comment on the answers given in the technical report, as appropriate.
B. On the basis of the German communication, the CSTEE is hereby asked whether the reasons put forward by the German Government:
- represent or contain new scientific evidence which has arisen after 5 December 1997,
- whether this scientific evidence - if it exists - relates to the protection of the environment or the working environment on grounds of a problem which is specific to the Federal Republic of Germany,
Comment from the CSTEE: A scientific evaluation of either document (the German communication and the Technical report) is made difficult by the lack of references to the scientific literature. The text of both documents (particularly that of the Technical Report) mixes allusions to scientific findings and to their potential normative consequences, without a clear distinction between the two.
Comments to the major criticisms of the Technical Report to the German Communication
1. Differences in criteria given by Directives 97/69/EC and 67/548/EEC (Annex VI) on the classification of mineral wools as carcinogens.
The German communication (paragraph II 1 a)) states that the former but not the latter permits a maximum classification of the evidence of carcinogenicity in category 3 and supports this statement with two examples, regarding respectively fibre types 475 and E. The Technical Report (I.(a) (i)) argues about the validity of the two examples, but does not comment on whether or not Directive 97/69/EC does indeed prevent the classification in category 2 for mineral wool with alkaline oxide and alkali earth oxide content greater than 18% by weight.
Neither document comments on the fact that glasswool - another man made mineral fibre - is classified by the EC in category 3 whereas in the US, since 1994, the Annual Reports on Carcinogens released by NIEHS/NTP classify this agent among those which can "reasonably be anticipated to be human carcinogens".
2. Route of administration in carcinogenicity tests.
The German communication (paragraph II 1 aa) recalls doubts expressed by part of the scientific community (ndr such as IARC) on the consideration of long term inhalation studies as necessarily the most sensitive tests for the identification of airborne carcinogens. The Technical report (I.(b) (aa)) does not address these uncertainties, but apodictically states in general terms that inhalation mimics more appropriately the conditions of human intake. Actually, the Technical report endorses an unpublished statement supporting the relevance of a 90-day inhalation toxicity experimental study. Although based on scientifically sound hypotheses and preliminary data, the 90-day inhalation study still needs validation and standardisation and will not provide valuable data before several years.
On the contrary, the German communication suggests the validity of animal tests through administration of the agent (at appropriate doses) by the intraperitoneal routes whereas the Technical report does not provide biological (or statistical) data supporting a species-specific mechanism of action of agents producing cancer through the intraperitoneal route. The German communication is consistent with the opinion expressed by an IARC Working Group as recently as in 1996 (Kane AB et al. eds: Mechanisms of Fibre Carcinogenesis. IARC Scientific Publications N. 140) whose consensus report states that (p. 6)
"The major point of difference regarding the value of inhalation versus injection studies relates to their sensitivity and the applicability of results for predicting human hazard and risk. The point of major importance with respect to mechanisms of fibre carcinogenicity relates to the issue of dose, as mechanisms at high-dose levels may be different from those at low-dose levels. Although all techniques may be of use in examining particular aspects of the carcinogenic process from a mechanistic point of view, it needs to be considered that after deposition in the respiratory tract, translocation of fibres from the alveolar region to the pleura represents a selection process in terms of fibre dose and fibre size. This aspect is circumvented with direct intracavitary administration of fibres"
3. Restriction of consideration of biopersistence to fibres with a length > 20 micra.
The Technical report recalls that there is a consensus that long fibres "predominate" among those which "... are associated with pathogenicity/carcinogenicity". Whereas such consensus in fact exists, the Technical report does not comment on the scientific findings of Roedelsperger K, quoted in the German communication, which seem to suggest an autonomous, and different, role of shorter fibres in the predictive value of biopersistence tests.
4. Use of "weighted half time" (WT 1/2) for the determination of biopersistence
The Technical report (Additional scientific arguments) dismisses approaches alternative to the WT1/2 and ignores findings suggesting the slow clearance as a proper indicator of the biological behaviour of fibres [Jensen SL, Guldberg M: The influence of retained mass (lung burden) on the results of intratracheal tests. Occup Environ Med 1997; 54: 358-359 (letter)].
Furthermore, under I (b) (bb), the Technical Report (Additional scientific arguments) alludes to a method - using CONFOCAL microscopy - recently developed for determining whether agglomeration is present following intratracheal administration of 2 mg fibre and for quantifying such agglomeration. According to the Technical Report,
"if this method were incorporated into the intratracheal protocol, then a single dose of a total 2 mg (given 4 times at sub-doses of 0.5 mg) which results in less than 10% agglomeration could be acceptable".
Since no references are given, the CSTEE is not in a position of verifying the validity of the method.
5. Predictivity of the KI index:
Although the KI index has been developed from an evaluation of available experimental data, it has not been extensively tested to confirm that the chemical composition of a fibre is informative about its carcinogenicity. The CSTEE is aware of a recent study performed at the Fraunhofer Institute in Hanover which suggests that fibres with different persistence measured in vivo may have the same KI ( Bellmann B, Muhle H: The biopersistence of MMVFs Exp 43 and Exp44 after intratracheal instillation in rats. A comparison of two fibres with high carcinogenicity index (KI) Final Report, Rockwool Study No. Ri-1995023, October 1997). It seems that these observations were not taken into account by the authors of the Technical Report.
6. Overall evaluation of the carcinogenicity of man-made mineral fibres (MMMF)
Annexes 1-8 to the German Communication (pages 10-11) run over again opinions on the risks created by MMMF, which have been expressed in Germany over the last few years (the most recent dating from November 1997), which have led to the acceptance by manufacturing industries that "only man-made mineral fibres are marketed in Germany which are sufficiently bio-soluble". Emphasis is also given to the fact that, given the many users of mineral wool and the risks entailed by exposure in the absence of any warning, it is preferable to err on the side of safety in terms of health protection.
Neither these general conclusions, nor the annexes to the German communication are given any comment in the Technical Report.
A note of the CSTEE on epidemiological observations on the carcinogenicity of man-made mineral fibres
As far as mineral wool is concerned (which is specifically mentioned in the terms of reference given from DG XI to CSTEE), it is surprising that neither the German communication nor the Technical Report quote recent epidemiological findings on a large cohort of producers of different types of man-made mineral fibres (Boffetta P, Saracci R, Anderson A, Bertazzi PA, Chang-Claude J, Cherrie J, Ferro G, Frentzel-Beyme R, Hansen J, Olsen J, Plato N, Teppo L, Westerholm P, Winter PD, Zocchetti C. Cancer Mortality among Man-Made vitreous fibre production Workers. Epidemiology 1997; 8(3):259-268).
The authors' conclusion is that
"a carcinogenic effect of exposure occurring in the rock/slag working environment is a credible explanation of the findings, although a contribution from tobacco smoking and occupational exposure in other working milieus cannot be wholly excluded. ... exposure to asbestos might have been elevated in one plant .... The excess was also present, however, in the other factories. These results are not sufficient to conclude that the increased lung cancer risk is related specifically to exposure to man made vitreous fibres, however, insofar as respirable fibres were an important component of the ambient pollution of the working environment, they may have contributed to the increased risk"
Results provide limited evidence of carcinogenicity of rock/slagwool to humans , i.e. (according to the definition of IARC) "a positive relationship between exposure and cancer ... in studies in which chance, bias and confounding could not be ruled out with reasonable confidence". It is reasonable to believe that these findings are among those which "have raised concern over the health effects of man-made vitreous (silicate) fibres" which are mentioned in the text of Directive 97/69/EC.
In a discussion of provisions that divert from Directive 97/69/EC with regard to classification and labelling of mineral wool, consideration of these findings cannot be dismissed. More generally, the question arises about the degree of substantiation required from suggestive (albeit not probative) epidemiological evidence of carcinogenicity in order to correspond to the "other relevant information" leading to the classification of an agent as a Category 2 carcinogen.
Answers of the CSTEE to the questions put in the terms of reference
A. The Technical Report does not provide convincing scientific evidence for confuting the arguments put forward in the German communication. Whether this inadequacy is factual or simply reflects the format of the Technical Report would require an ad hoc review of the literature.
B. - The reasons put forward by the German Government do not specifically allude to any scientific evidence which has arisen after 5 December 1997.
- As for mineral wools, epidemiological findings published in 1997 confirm that there is evidence - albeit limited - that exposure to rockwool/slagwool is carcinogenic for the human lung.
- The relevant scientific evidence mentioned in the present document relates to the protection of the working environment on grounds of a problem which is not specific to the Federal Republic of Germany.
Terms of reference
A. On the basis of the Communication from the Government of the Federal Republic of Germany to the European Commission of 11 December 1998 (heretofore indicated as "German communication"), justifying the reasons why the German Government intends to incorporate national provisions that divert from Directive 97/69/EC which contains, among others, the classification and labelling of mineral wool, the CSTEE is hereby asked whether the answers contained in the document "Technical Report on the reasons put forward by the Federal Republic of Germany for applying national provisions which divert from the requirements of Directive 97/69EC, the 23rd Adaptation to technical progress of Council Directive 67/548 EEC (heretofore indicated as "Technical Report") correctly address the arguments put forward in the German Communication. The CSTEE is invited to comment on the answers given in the technical report, as appropriate.
B. On the basis of the German communication, the CSTEE is hereby asked whether the reasons put forward by the German Government:
- represent or contain new scientific evidence which has arisen after 5 December 1997,
- whether this scientific evidence - if it exists - relates to the protection of the environment or the working environment on grounds of a problem which is specific to the Federal Republic of Germany,
Comment from the CSTEE: A scientific evaluation of either document (the German communication and the Technical report) is made difficult by the lack of references to the scientific literature. The text of both documents (particularly that of the Technical Report) mixes allusions to scientific findings and to their potential normative consequences, without a clear distinction between the two.
Comments to the major criticisms of the Technical Report to the German Communication
1. Differences in criteria given by Directives 97/69/EC and 67/548/EEC (Annex VI) on the classification of mineral wools as carcinogens.
The German communication (paragraph II 1 a)) states that the former but not the latter permits a maximum classification of the evidence of carcinogenicity in category 3 and supports this statement with two examples, regarding respectively fibre types 475 and E. The Technical Report (I.(a) (i)) argues about the validity of the two examples, but does not comment on whether or not Directive 97/69/EC does indeed prevent the classification in category 2 for mineral wool with alkaline oxide and alkali earth oxide content greater than 18% by weight.
Neither document comments on the fact that glasswool - another man made mineral fibre - is classified by the EC in category 3 whereas in the US, since 1994, the Annual Reports on Carcinogens released by NIEHS/NTP classify this agent among those which can "reasonably be anticipated to be human carcinogens".
2. Route of administration in carcinogenicity tests.
The German communication (paragraph II 1 aa) recalls doubts expressed by part of the scientific community (ndr such as IARC) on the consideration of long term inhalation studies as necessarily the most sensitive tests for the identification of airborne carcinogens. The Technical report (I.(b) (aa)) does not address these uncertainties, but apodictically states in general terms that inhalation mimics more appropriately the conditions of human intake. Actually, the Technical report endorses an unpublished statement supporting the relevance of a 90-day inhalation toxicity experimental study. Although based on scientifically sound hypotheses and preliminary data, the 90-day inhalation study still needs validation and standardisation and will not provide valuable data before several years.
On the contrary, the German communication suggests the validity of animal tests through administration of the agent (at appropriate doses) by the intraperitoneal routes whereas the Technical report does not provide biological (or statistical) data supporting a species-specific mechanism of action of agents producing cancer through the intraperitoneal route. The German communication is consistent with the opinion expressed by an IARC Working Group as recently as in 1996 (Kane AB et al. eds: Mechanisms of Fibre Carcinogenesis. IARC Scientific Publications N. 140) whose consensus report states that (p. 6)
"The major point of difference regarding the value of inhalation versus injection studies relates to their sensitivity and the applicability of results for predicting human hazard and risk. The point of major importance with respect to mechanisms of fibre carcinogenicity relates to the issue of dose, as mechanisms at high-dose levels may be different from those at low-dose levels. Although all techniques may be of use in examining particular aspects of the carcinogenic process from a mechanistic point of view, it needs to be considered that after deposition in the respiratory tract, translocation of fibres from the alveolar region to the pleura represents a selection process in terms of fibre dose and fibre size. This aspect is circumvented with direct intracavitary administration of fibres"
3. Restriction of consideration of biopersistence to fibres with a length > 20 micra.
The Technical report recalls that there is a consensus that long fibres "predominate" among those which "... are associated with pathogenicity/carcinogenicity". Whereas such consensus in fact exists, the Technical report does not comment on the scientific findings of Roedelsperger K, quoted in the German communication, which seem to suggest an autonomous, and different, role of shorter fibres in the predictive value of biopersistence tests.
4. Use of "weighted half time" (WT 1/2) for the determination of biopersistence
The Technical report (Additional scientific arguments) dismisses approaches alternative to the WT1/2 and ignores findings suggesting the slow clearance as a proper indicator of the biological behaviour of fibres [Jensen SL, Guldberg M: The influence of retained mass (lung burden) on the results of intratracheal tests. Occup Environ Med 1997; 54: 358-359 (letter)].
Furthermore, under I (b) (bb), the Technical Report (Additional scientific arguments) alludes to a method - using CONFOCAL microscopy - recently developed for determining whether agglomeration is present following intratracheal administration of 2 mg fibre and for quantifying such agglomeration. According to the Technical Report,
"if this method were incorporated into the intratracheal protocol, then a single dose of a total 2 mg (given 4 times at sub-doses of 0.5 mg) which results in less than 10% agglomeration could be acceptable".
Since no references are given, the CSTEE is not in a position of verifying the validity of the method.
5. Predictivity of the KI index:
Although the KI index has been developed from an evaluation of available experimental data, it has not been extensively tested to confirm that the chemical composition of a fibre is informative about its carcinogenicity. The CSTEE is aware of a recent study performed at the Fraunhofer Institute in Hanover which suggests that fibres with different persistence measured in vivo may have the same KI ( Bellmann B, Muhle H: The biopersistence of MMVFs Exp 43 and Exp44 after intratracheal instillation in rats. A comparison of two fibres with high carcinogenicity index (KI) Final Report, Rockwool Study No. Ri-1995023, October 1997). It seems that these observations were not taken into account by the authors of the Technical Report.
6. Overall evaluation of the carcinogenicity of man-made mineral fibres (MMMF)
Annexes 1-8 to the German Communication (pages 10-11) run over again opinions on the risks created by MMMF, which have been expressed in Germany over the last few years (the most recent dating from November 1997), which have led to the acceptance by manufacturing industries that "only man-made mineral fibres are marketed in Germany which are sufficiently bio-soluble". Emphasis is also given to the fact that, given the many users of mineral wool and the risks entailed by exposure in the absence of any warning, it is preferable to err on the side of safety in terms of health protection.
Neither these general conclusions, nor the annexes to the German communication are given any comment in the Technical Report.
A note of the CSTEE on epidemiological observations on the carcinogenicity of man-made mineral fibres
As far as mineral wool is concerned (which is specifically mentioned in the terms of reference given from DG XI to CSTEE), it is surprising that neither the German communication nor the Technical Report quote recent epidemiological findings on a large cohort of producers of different types of man-made mineral fibres (Boffetta P, Saracci R, Anderson A, Bertazzi PA, Chang-Claude J, Cherrie J, Ferro G, Frentzel-Beyme R, Hansen J, Olsen J, Plato N, Teppo L, Westerholm P, Winter PD, Zocchetti C. Cancer Mortality among Man-Made vitreous fibre production Workers. Epidemiology 1997; 8(3):259-268).
The authors' conclusion is that
"a carcinogenic effect of exposure occurring in the rock/slag working environment is a credible explanation of the findings, although a contribution from tobacco smoking and occupational exposure in other working milieus cannot be wholly excluded. ... exposure to asbestos might have been elevated in one plant .... The excess was also present, however, in the other factories. These results are not sufficient to conclude that the increased lung cancer risk is related specifically to exposure to man made vitreous fibres, however, insofar as respirable fibres were an important component of the ambient pollution of the working environment, they may have contributed to the increased risk"
Results provide limited evidence of carcinogenicity of rock/slagwool to humans , i.e. (according to the definition of IARC) "a positive relationship between exposure and cancer ... in studies in which chance, bias and confounding could not be ruled out with reasonable confidence". It is reasonable to believe that these findings are among those which "have raised concern over the health effects of man-made vitreous (silicate) fibres" which are mentioned in the text of Directive 97/69/EC.
In a discussion of provisions that divert from Directive 97/69/EC with regard to classification and labelling of mineral wool, consideration of these findings cannot be dismissed. More generally, the question arises about the degree of substantiation required from suggestive (albeit not probative) epidemiological evidence of carcinogenicity in order to correspond to the "other relevant information" leading to the classification of an agent as a Category 2 carcinogen.
Answers of the CSTEE to the questions put in the terms of reference
A. The Technical Report does not provide convincing scientific evidence for confuting the arguments put forward in the German communication. Whether this inadequacy is factual or simply reflects the format of the Technical Report would require an ad hoc review of the literature.
B. - The reasons put forward by the German Government do not specifically allude to any scientific evidence which has arisen after 5 December 1997.
- As for mineral wools, epidemiological findings published in 1997 confirm that there is evidence - albeit limited - that exposure to rockwool/slagwool is carcinogenic for the human lung.
- The relevant scientific evidence mentioned in the present document relates to the protection of the working environment on grounds of a problem which is not specific to the Federal Republic of Germany.
