THE ASBESTOS INSTITUTE

RAPPORT D'EXPERTISE COLLECTIVE
INSERM

    Effets sur la santé
    des principaux types d'exposition
    à l'amiante

    Rapport établi à la demande
    de la Direction des Relations du Travail
    et de la Direction Générale de la Santé, France

Paris, juin 1996

    Prepared by
       Jacques Dunnigan, PhD
    September 1996

    at the request of
    Service du développement minier,
    Ministère des Ressources naturelles
    Gouvernement du Québec

General comments
On the international scale, several renowned scientists, including the chief experts on asbestos, have been concerned about the use of mathematical methods to extrapolate to low doses the effects observed in man and animal at high concentrations of carcinogens, since such extrapolations have resulted in highly exaggerated mortality projections. Moreover, most of these alarmist projections have proven to be untrue. In addition, such methods have never been verified in clinical tests.

In their presentation of the INSERM report, requested by the Direction des Relations du Travail and the Direction générale de la Santé, entitled Effets sur la santé des principaux types d'expositions à l'amiante the authors said they could not reasonably ignore the great consolidation work achieved over the past ten years by expert government groups in the U.S., Great Britain and Canada. Obviously, the authors could not take into account the most recent update of the question prepared in Great Britain - specifically the report published in late summer 1996 by the Health & Safety Executive (HSE): Review of Fibre Toxicology - although they admit they were aware of its existence. This report - intended to represent the HSE's current position ("This review aims to present the HSE stance on fibre toxicology") - states that, while in 1985 the evaluation of the chrysotile asbestos-related lung cancer risk was based on a linear model with no threshold applied to the mortality data for asbestos textile industry workers, toxicological data as a whole does not support this no-threshold model for asbestos-induced cancer, and that in practice a threshold does exist.

"The Doll and Peto (1985) risk assessment for chrysotile-induced lung cancer was based on a linear no-threshold model applied to mortality data from chrysotile textile manufacture. However, the balance of toxicological evidence does not support the no-threshold model for asbestos-induced cancer. A practical threshold is likely". (Review of Fibre Toxicology, HSE, 1996)

The authors admit that they had been working to a deadline although the above-mentioned expert government groups took several years to complete their work. They also admit that, because of this deadline, the health risks associated with exposure to substitution fibres were not addressed, nor were problems concerning the technical properties of asbestos replacement. The authors are nevertheless of the opinion that, in terms of the asbestos ban option, "the problem is inextricably linked with the choice of replacement fibres", and add that the expert group "does not have sufficient information to judge the possibility of replacing asbestos with a substitution product that is free of risk in all cases".

It is thus easy to understand why the members of the committee insist, from the beginning of their report, that "management of these risks was not part of its mandate", and that they would make no declaration "on the relevance of regulatory exposure values, the ban option or systematic removal of asbestos from buildings . . ."

Comments on the mathematical model used to calculate the excess risk of lung cancer (LC) and mesothelioma (M) at low levels of exposure to chrysotile asbestos.

The authors used a linear model of cumulative exposure with no threshold; this model was the same for fibres from different geological sources. We believe that this sort of exercise is unjustified in several respects:

1. Linear threshold model
At low levels of exposure, the report relies on the linear aspect of the exposure-response curve commenting that, for them, it was the "the most plausible uncertain assumption". The resulting excess risk calculations for LC and M appear in Tables 3, 4 and 5, and are therefore the result of an option (linear, no-threshold) that is no more and no less plausible than any other option: sigmoid, with threshold. The report states: "We can therefore confidently assert that there is no argument based on direct or indirect existing epidemiological data to support the proposition that linear extrapolation with no threshold using data corresponding to higher levels of exposure to asbestos . . . is not the most plausible, although uncertain, model." (p. 39)

What the report does not say is that the "sigmoid with threshold" alternative can also be sustained. Using the same language, we can also confidently assert that there is no argument based on direct or indirect existing epidemiological data to support the proposition that sigmoid extrapolation with a threshold is not just as plausible, although uncertain. This was also Liddell's opinion as published in the monograph entitled "Mineral Fibres and Health" (1991, CRC Press, eds. Liddell, D. and Miller, K.), where he says: "cumulative exposure is by no means necessarily the most appropriate index for determining the exposure-response relationship. In particular, that index disallows a "threshold", which Vacek and McDonald show to be a viable concept". The authors of the INSERM report recognize that ". . . the exact form (linear, supra-linear, intralinear) of the dose-risk relationship is not known for levels less than 1 f/ml . . ." (p. 55)

Estimates of the excess risk of LC and M at an exposure of 0.1 f/ml have therefore been based on one plausible model among others. Without dwelling on the dubious scientific justification for extrapolating over more than three orders of magnitude (250 f/ml to 0.1 f/ml), we believe that what such a mathematical exercise shows is the inability of the method used to provide credible information on the risk of low-level exposure to chrysotile asbestos.

We feel it is unfortunate that the group assembled by INSERM engaged in an exercise that was not only selective, but unwise as well, in the sense that it could lead to risk management decisions inspired by the dubious results of selective mathematical exercises. Furthermore, the INSERM report recognizes this possibility: "This extrapolation does not produce definitive scientific information; it represents a tool for reflection in risk management". (p. 46).

It would have been better if INSERM had not rushed to deliver its report (despite the tight deadline) and had also taken into account recently published concrete data (Appendix 1) that show the absence of excess risk at chrysotile asbestos exposure levels of around 1 f/ml.

2. A cumulative exposure model
With respect to asbestos exposure levels (Section 1.6), the authors report data for France in different circumstances - urban and rural environments, geological and industrial sites, indoors. However, the authors point out that "the values cited are orders of magnitude" and they add ". . . at the present time, there is no published data that would provide even approximate knowledge of the cumulative asbestos exposure levels for individuals in each of the circumstances cited or the distribution of the French population among these categories (either in number or duration)". (p. 18)

The authors clearly state that ". . . to establish an exposure-effect relationship and quantify the risk associated with various exposure levels, the exposure level for each subject included in the study must be evaluated". (p. 28)

To compensate for this shortcoming, the authors use a job-exposure matrix method or something similar. An evaluation is made of the average exposure level for a given situation, and the subject's history is then compared with this matrix to calculate the various individual exposure indices (average level, cumulative level, etc.). These individual exposure level calculations were used to quantify LC and M risks in terms of exposure levels.

One can wonder, then, what degree of uncertainty this mathematical short-cut introduces into the LC and M risk quantification exercise which, it must be remembered, is based on cumulative exposure data.

It should be noted again that the question still remains open - is a model based on cumulative exposure valid for chrysotile asbestos whose biopersistence is estimated to be several weeks or months at the most, while, for all practical purposes, amphiboles persist indefinitely?

Comments on the "amphibole hypothesis" mentioned in the report
The report mentions the publication by Mossman et al. (1990) with respect to what some have called the "amphibole hypothesis". According to the report, "the hypothesis that chrysotile asbestos is not carcinogenic. . ." was formulated by the authors of this publication. However, a careful reading shows that the authors never made such a statement. Instead, they took into account the numerous data available in the late 1990s simply to highlight what had been the subject of a broad consensus in the international scientific community - that amphiboles presented a greater pathogenic potential than chrysotile asbestos in every respect. This consensus has never been seriously challenged to this day, witness, for example, the conclusion of a 1994 Swedish publication (Albin et al., 1994) in which the authors state that their study . . .

". . . supports a former finding of a possible adaptive clearance of chrysotile, and . . . supports the hypothesis that adverse effects are associated rather with the fibres that are retained (amphiboles), than with the ones being cleared (largely chrysotile)".

We have said that amphiboles present a greater potential in every respect. In fact, this exact wording was used in 1986 by one of the best known experts on asbestos, Dr. John C. Wagner (Wagner, JC and Pooley, FD, 1986):

". . . we believe that chrysotile is the least harmful form of asbestos in every respect, and that greater emphasis should be placed on the different biological effects of the various amphibole fibres."

A comment on this point is appropriate. Most experimental studies, both in vitro and in vivo, published up to the early 1980s and even later did not allow for a distinction between the pathogenic potential of the different types of asbestos. Experimental results did not seem to agree with those of epidemiological studies which clearly showed a much greater potential for amphiboles to induce asbestosis, lung cancer and mesothelioma. However, a close examination of the experimental protocols used up until that time shows that the comparison of experimental effects (cytotoxicity, fibrogenesis, neoplasms) was based on gravimetric doses in most cases; i.e., effects/fibre mass unit. A posteriori calculations showed that if the effects had been reported by number of fibres, the data would have indicated that, fibre for fibre, chrysotile asbestos is indeed less pathogenic than amphiboles. Thus, in 1988, experts from the U.S. EPA published the results of a comparison of in vitro cytotoxic effects based on doses expressed in gravimetric terms and in number of fibres (Palekar et al., 1988). The values of the toxicological effects of erionite, crocidolite, and chrysotile were in a ratio of 1/6/350, respectively. In other words, in the protocol used, a greater number of chrysotile fibres were required to produce the same quantitative effects of erionite and crocidolite.

More recently, experimental studies presenting results expressed in terms of mass as well as in number of fibres indicate that the experimental models show that, fibre for fibre, amphiboles are more pathogenic than chrysotile asbestos. This was confirmed in recently used in vitro models (Yegles et al., 1993; Heintz et al., 1993; Mahmood et al., 1994) as well as in one in vivo model in which inhalation experimentation showed that crocidolite is more fibrogenic and carcinogenic than chrysotile asbestos (McConnell et al., 1994). References mentioned in this section appear in Appendix 2.

In our general comments, we indicated that the authors of the INSERM Report claim to have taken into account certain studies by expert government groups. We would add that we are not certain that they seriously considered the evaluation made by a group of experts assembled by the World Health Organization in Oxford in 1989 under the chairmanship of a renowned epidemiologist, Sir Richard Doll. Upon completion of their analysis, this group of experts made two recommendations, among others, which they felt were appropriate for occupational hygiene standards for asbestos: 1 f/ml for chrysotile asbestos, and the banning of all amphibole fibres. In formulating their recommendations, the group of experts indicated that these recommendations were "based on health reasons alone", i.e., on biological responses and not on any administrative consideration or technological constraint for fibre measurement. To our knowledge, since this in-depth analysis by the group of experts that brought together the chief international experts on asbestos - including some French experts participating in INSERM's "collective expertise" - no new data has appeared that would cast doubt on the group's evaluation. On the contrary, several follow-ups published since then have only confirmed its validity.

Conclusion
In conclusion, we feel that the INSERM report alone does not provide sufficiently credible and complete basis for concluding that the only way to protect the health of workers and the general public is, purely and simply, to totally ban all varieties of asbestos and all its applications.

The authors of the report themselves admit that the methodological basis used to produce the low-level exposure risk data for chrysotile asbestos could not produce "definitive scientific information".
Assuming that the report could provide a basis for a risk-management decision to ban all varieties of asbestos, such a decision, without credible scientific justification, would be at variance with the analysis in 1989 by the group of experts assembled at Oxford under the auspices of the World Health Organization (WHO), whose recommendations in terms of asbestos fibres were to keep workplace emissions at a level of 1 f/ml (weighted average over eight hours) for chrysotile asbestos and to ban amphibole varieties. We know of no new data published since that date that would be likely to change this analysis or its recommendations. On the contrary, the most recent data published (McDonald et al., 1993) support the validity of these recommendations.
Furthermore, we believe that while it is appropriate to ban some uses of chrysotile asbestos (e.g., friable materials), this does not apply to other uses such as asbestos cement, in which fibres are bound in such a way that there is practically no risk of emission at unacceptable levels, using known and proven control technologies. We believe that monitoring and compliance with the standard are better guarantees of protection than blindly resorting to substitution fibres whose long-term effects are not sufficiently known, as the authors of the INSERM report themselves acknowledge in the introductory chapter.
As for risks to the general public associated with the presence of asbestos in buildings, we believe that consideration should be given to estimates based on the very broad studies conducted primarily in the U.S., Great Britain and Canada that indicate that at the concentrations measured, the risk is insignificant. The risk was described as "not significant" (ORCA), "acceptable" (WHO) and the Royal Society (London) felt that ". . . further control (is) not justified".
The risk-management priority associated with the presence of asbestos in buildings should therefore focus on protecting workers in the various building trades involved in repair, renovation and demolition. Complete programs for managing this type of risk should be implemented. We suggest that it would be well worthwhile in this regard to have an open discussion between the competent authorities in Québec and France in which the exchange of expertise and practical experience would be of benefit to all parties concerned.

Jacques Dunnigan
1996

"Those who demand the removal and substitution of all asbestos, irrespective of fibre types or level of contamination, should note that removal can actually increase cumulative exposure to both workers and occupants, and that substitutes for asbestos may be less innocuous than has generally been assumed. The campaign to eliminate all asbestos on the grounds that 'one fibre can kill', besides being a cost-benefit absurdity, may thus actually increase the risk." (Peto, J. in IARC Scientific Publication No. 90, Lyon 1989, p. 457-469)

Appendix 1

Recent epidemiological studies on cohorts of workers
exposed to low levels of chrysotile asbestos

Berry, G and Newhouse, ML (1983). Mortality of workers manufacturing friction materials using asbestos. British Journal of Industrial Medicine 40(1):1-7.

Mortality study (1920-1980) of workers in a friction materials plant in Great Britain where chrysotile asbestos was used almost exclusively. The authors detected no excess deaths from lung, gastrointestinal or other cancers in comparison with national death rates. Exposure levels were low, with only 5% of the workers accumulating 100 f/ml per year. The authors concluded that "The experience at this factory over a 40-year period showed that chrysotile asbestos was processed with no detectable excess mortality".

Newhouse, ML and Sullivan, KR (1989). A mortality study of workers manufacturing friction materials: 1941-86. British Journal of Industrial Medicine 46(3):176-179.

Update of previous study with a seven-year follow-up. The authors confirm that there was still no excess of lung cancer or other cancers, or excess of chronic pulmonary illnesses. They indicate that, after 1950, health conditions improved gradually, with exposure levels reaching about 0.5 to 1.0 f/ml in 1970. They conclude that "with good environmental control, chrysotile asbestos may be used in manufacture without causing excess mortality".

Thomas, HF, Benjamin, IT, Elwood, PC and Sweetnam, PM (1982). Further follow-up study of workers from an asbestos cement factory. British Journal of Industrial Medicine 39(3):273-276.

Update of follow-up of asbestos cement plant workers using only chrysotile asbestos. The cohort included 1970 workers. No statistically significant excess was detected for the causes analysed: all causes, all neoplasms, cancers of the lung, bronchus and digestive tract. The authors conclude: "Thus the general results of this mortality survey suggest that the population of the chrysotile asbestos cement factory studied are not at any excess risk in terms of total mortality, all cancer mortality, cancers of the lung and bronchus, or gastrointestinal cancers".

Weill, H, Hughes, J and Waggenspack, C (1979). Influence of dose and fibre type on respiratory malignancy risk in asbestos cement manufacturing. American Review of Respiratory Disease 120(2):345-354.

Study of 5,645 asbestos cement plant workers in the U.S. showing no excess mortality that could be associated with exposure for 20 years or more at an exposure level less than or equal to 100 f/ml per year. The authors conclude: "However, the demonstration that low cumulative short-term exposures did not produce a detectable excess risk for respiratory malignancy may be of assistance in the development of regulatory policy, because a scientifically defensible position based on these data is that there are low degrees of exposure not associated with a demonstrable excess risk".

Ohlson, CG and Hogstedt, C (1985). Lung cancer among asbestos cement workers. A Swedish cohort study and a review. British Journal of Industrial Medicine 42(6):397-402.

Study of a cohort of 1,175 asbestos cement plant workers in Sweden. No excess mortality was observed at exposure levels estimated at 10 - 20 f/ml per year.

McDonald, JC, Liddell, FDK, Dufresne, A and McDonald, AD (1993). The 1891-1920 birth cohort of Quebec chrysotile miners and millers: mortality 1976-88.
British Journal of Industrial Medicine 50:1073-1081.

Undoubtedly the largest cohort of workers exposed to chrysotile asbestos and the one with the longest follow-up. The cohort was established in 1996 and includes approximately 11,000 Québec chrysotile mine workers born between 1891 and 1920. Every effort was made to establish exposure levels in an optimum manner for each member of the cohort in terms of duration and intensity. The results on mortality were published on five occasions, the most recent update focusing on the 1976-1988 period. The central finding of this latest update is to the effect that, in several restricted categories of exposure levels up to 300 mppc per year, the SMR for lung cancer fluctuated around 1 with no evidence of a trend, but began to rise after this level. By applying the conservative conversion factor of 1 mppc ~ 3 f/ml, this recent update provides a credible basis for the recommendation made by the group of experts assembled at Oxford in 1989 by the WHO, which recommended a standard of 1 f/ml for chrysotile asbestos.

Appendix 2

Albin A, Pooley FD, Strömberg U, Attewell R, Mitha R andWelinder H (1994). Retention patterns of asbestos fibres in lung tissue among asbestos cement workers. Occup. Environ. Med. 51: 205- 211.

Heintz NH, Janssen YM and Mossman BT (1993). Persistent induction of c-fos and c-jun expression by asbestos, Proc. Natl Acad Sci 90: 3299-3303.

Mahmood N, Khan SG, Athar M, Rahman Q (1994). Different role of hydrogen peroxide and organic peroxides augmenting asbestos-mediated DNA damage - Implications for asbestos induced carcinogenesis. Biochem Biophys Res Comm 200: 687 - 694.

McDonald, JC, Liddell, DK, Dufresne, A and McDonald, AD (1993). The 1891-1920 birth cohort of Quebec chrysotile miners and millers: mortality 1976-88. Brit. J. Ind. Med. 50: 1073-1081.

McConnell EE, Chevalier HJ, Hesterberg TW, Hadly JG and Mast RW (1994).
In ILSI Monograph "Toxic and carcinogenic effects of solid particles in the respiratory tract", eds. DL Dungworth, JL Mauderly and G. Oberdörster, ILSI Press, pp. 461-467.

Palekar LD, Most BM, Coffin DL (1988). Significance of mass and number of fibers in the correlation of V79 cytotoxicity with tumorigenic potential of mineral fibers. Environ Res 46: 142 - 152.

Wagner JC and Pooley FD (1986). Mineral fibres and mesothelioma. Thorax 41: 161-166.

Yegles M, St-Etienne L, Renier L, Janson X and Jaurand MC (1993). Induction of metaphase and anaphase abnormalities by asbestos fibers in rat pleural mesothelial cells in vitro. Amer. J. Resp. Cell Mol. Biol.9: 186-191.

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