Human and Experimental Studies of RCF Toxicity

Transcription

1 Human and Experimental Studies of RCF Toxicity Regulatory controls on RCF result from misunderstanding of the experimental data. Prof. Robert C. Brown Ph.D Toxicology Services 6 Stocken Hall Mews, Stretton, Rutland, UK, LE15 7RL Summary Refractory Ceramic fibres (RCF) are glass wools mainly used in applications like the lining of industrial furnaces. RCFs are often described as being similar to asbestos and thus more likely than other glass wools to cause disease. However this view is based on a series of misunderstandings. Studies in RCF manufacturing companies have not found any convincing evidence of effects of RCF exposure on either chest x-ray appearance or lung function. When we exclude data from animal experiments in which the maximum tolerated dose was exceeded we conclude that that the pathogenicity of all fibres depends only on the number of fibres of equal length present in tissue. Fibre diameters determine the number of fibres reaching the lung; tissue dose is then a function of the ability of the fibres to persist in tissue. RCFs have biopersistence values very similar to many other man made fibres. Introduction Refractory ceramic fibres (RCF - CAS No ) are aluminosilicate glass wools. They are fibrous, synthetic, vitreous silicates; they therefore belong to the same class of materials as the glass, rock (stone) and slag wools, and also the special-purpose glass fibres. There is no universally accepted, accurate, taxonomy of these materials so that experimental results from one type have often been ascribed to others for no good reason. For example in 1988 [1] the review of fibre carcinogenicity by IARC included crystalline whiskers and some crystalline fibres under the title ceramic fibre, a decision for which there was no material science justification. This problem was avoided in the IARC 2002 monograph [2], which only considered vitreous fibres. However some properties of the whiskers, such as their high biopersistence, continue wrongly to be ascribed to RCF. In this review only RCFs that are members of the group defined by CAS will be considered. The danger of the linguistic determinist approach [3] can be seen in the results of using the terms ceramic rather than glass and fibre rather than wool. This has lead to the as-

2 sumption that RCFs must have completely different properties to the other glass wools. In fact apart from their high melting point no chemical or physical properties unique to the RCFs have been discovered. The glass wools have a continuum of compositions within which the European Union felt a compulsion to distinguish between more and less hazardous types. They therefore divided the carcinogen classification between categories 2 and 3 at an arbitrary, and unscientific, composition boundary whose main advantage seemed to be to exclude the common building insulation wools from the more hazardous class [4]. The regulatory distinction was triggered only an uncritical assessment of one set of animal experiments Health concerns and the industry s responses. High temperature insulation requires, radiant heat, that is the infrared light emitted by the hot source, to be blocked in turn this requires fibres with similar diameters to the wavelengths of this light. Therefore RCFs are necessarily finer than many other glass fibres. While RCFs are less soluble than most other commercial wools, at least at neutral ph, they are also more friable. The combination of friability and low diameter means that when handled, RCF wools can liberate respirable fibre fragments to which humans could be exposed. This led the manufacturers to establish a substantial product stewardship programme to safeguard the health of its workers and customers. As well as developing new products [5, 6] this programme has involved inter alia :- Health studies in manufacturing; a longitudinal morbidity study in the USA [7, 8] and two cross sectional studies in Europe [9,10]. A large number of animal studies including long-term rat and hamster inhalation studies [11,12,13], subchronic (90 day) studies [14,15] and other short-term rat studies [16]. Developing estimates of human risk, using various methods and models [17,18,19]. Highly structured occupational hygiene efforts in both Europe and the USA; aimed at measuring and reducing workers exposures in both manufacturing and customers premises [20,21 and see Class in this volume]. This review will concentrate on the first two points above. The health of Workers in RCF manufacturing plants Morbidity studies have been carried out on workers in RCF manufacturing in both Europe and in the United States. Both lung function and chest x-ray appearance have been monitored. The only effects of RCF were significant deficits in expiratory lung function in smokers and ex-smokers, but not neversmokers [9,10,22]. Interestingly this is consistent with the report of lung function changes in

3 rockwool workers [23]. While the effect of exposure was clear in the results from early lung function tests the difference did not worsen on follow up. That is for individual RCF workers who provided five or more pulmonary function tests between 1987 and 1994 there was no decline between the first and last tests in either FVC or FEV 1 [8]. Lockey and his co-authors conclude that the initial effect was due to higher exposures in the 1980 s. There is no convincing evidence that current occupational exposure levels result in lung function changes. Chest x-ray studies have not demonstrated any RCF related increase in interstitial fibrosis; x-ray opacities were similar to other workers [7] or to a non-dust exposed group [10]. However in the early US studies pleural plaques were found in 27 of 625 current and 383 former RCF manufacturing workers. This overall incidence of 2.7% is lower than that found in many studies in the general public however the incidence was 8.0% among employees with more than 20 years from first job in RCF production. The first European study of RCF workers could find no clear association between exposure and x-ray abnormalities of any type The authors state that it seems unlikely that fibre exposure was the main or sole cause of radiographic abnormalities [24]. There was no unequivocal effect of RCF exposure on plaque incidence in the second European study [10] the results were sensitive to the inclusion of age and to the corrections for asbestos exposure. Thus if there was an effect it was very small. Interestingly the x-ray readers in this study were given films blind these included some from non-dust exposed workers, they found ten times more low-level interstitial abnormalities in these control films that when they were read previously. Without these controls an effect would have been seen. We do not know if pleural changes were read with the same preconceptions and thus level of bias? Mortality studies, with associated mortality registers, are the best way to detect any carcinogenic effect; but only one small study has been reported [25]. There was no excess mortality due to any cause, to any cancer or to diseases of the respiratory system. Walker et al. [26] compared the power of this study with the data on the incidence of lung cancers, including mesothelioma, in asbestos exposed populations. They found that the hypothesis that RCF is as potent as amphibole asbestos could be rejected. There is insufficient data to refute the hypothesis that it is as potent as chrysotile. The collection of mortality data continues and it would be advantageous to increase the scope of this, or other mortality, studies. Animal studies RCF was first examined in an animal test in the 1950 s before it was made commercially available; it was found to behave like an inert dust [27]. However this finding was not confirmed in a second inhalation study [28] in which 48 rats were exposed to 95 RCF fibres (longer than 5 µm)/cc, for seven hours a day, five days a week, over 12 months.

4 At the end of the study animals has an average of 5% pulmonary fibrosis, and eight were found to have pulmonary tumours (three carcinomas.) There was also one peritoneal mesothelioma. This result was difficult to interpret but naturally concerned the manufacturers who therefore commissioned a larger animal study on both hamsters and rats at the Los Alamos laboratory. In this study [29] the animals were exposed to RCF at 200 f/cc, 6 hours a day, 5 days a week for 24 months. The rats developed minimal fibrosis and there was no significant increase in tumours. In the fifty exposed hamsters no fibrosis was observed but there was one mesothelioma. This result was still felt to be equivocal and the RCF industry undertook an even larger range of studies that were eventually carried out at RCC in Geneva. These involved inhalation exposure of groups of rats and hamsters to a kaolin based RCF at 30mg.m -3. Similar rat groups were exposed to the same gravimetric concentration of a high purity fibre, a fibre containing 15% zirconia and to a mock after-use fibre. The kaolin sample was later used in rats at 3 further exposure concentrations. The results of these experiments have been published many times, including in several recent reviews [30,31]. Briefly only the groups of rats exposed at 30mg.m -3 to the kaolin and high purity fibres developed significant numbers of lung tumours. In the other groups the numbers of such tumours were comparable with historic control values for the strain of rats used. Several mesotheliomas occurred in the rats but also in nearly 40% of the hamsters. These mesothelial tumours were unusual, they were small and did not reduce the average life span of the hamsters. Fibrosis occurred in a way related to time and exposure. The early results of these experiments were sufficient to persuade the manufacturers of other vitreous silicate wools to undertake their own similar studies. A sample of rock, one of slag and two samples of glass wool were tested in rats alone. These studies have generally, but not universally, been regarded as negative. It is worth noting that therefore the total testing of RCFs covered a wider ranger of that industry s production than was the case for the other wools. Unlike many toxicology investigations those with fibres depend in part, perhaps the main part, on the size and shape of the fibres tested. They do not depend only, and in some cases not at all, on the chemical composition of the test article. While this is obvious after inhalation exposures it is best seen, and best quantified, in studies of the occurrence of mesothelial tumours after injection of fibrous dusts into the body cavities of rats. The most important variable determining potency is fibre length. The role of which was first quantified by Stanton [32]; however his results are often misinterpreted to suggest that all fibres above 8µm long are equally potent. The most complete data comes from the extensive body of

5 work by Pott using intraperitoneal (IP) injection. By plotting data from Burdett [33] figure one shows Pott s summary of the effect of length on carcinogenic potency. Figure one: Pott s potency model for the length of fibres injected intraperitonealy; with the average length of the RCC and UICC samples indicated The potency of fibres after intraperitoneal injection has been used to compare different materials however often insufficient attention has been paid to the role of varying length. In Germany in particular it became common to regard all fibres fitting the WHO counting criterion as equally active. This is one source of differences between EU and German regulations. The use of animal data in regulation. Perhaps the biggest problem in carrying out any animal experiment is the preparation of the test samples from the original glass wools, especially in the large quantities needed for inhalation studies. To do this requires the fibres to be shortened and the finer fibres isolated; this can easily result in an inert sample containing too many short fibres. The samples for the RCC experiments were carefully prepared so that the distributions of fibre sizes resembled that in the air at workplaces handling the wools. The RCF samples were isolated at the Carborundum Company (now Unifrax) while the so-called MMVF samples (rock, slag and glass wools) were prepared at the Manville Corporation using a different process. The two sets of samples were not identical; the glass wool samples were significantly shorter and all the RCF samples were contaminated with up to 30% by weight of non-fibrous dust. This is not typical of workplace air.

6 When laboratory rodents have very large lung burdens of even the most inert dust macrophage mediated clearance is overwhelmed, inflammation develops and this leads to fibrosis and tumours. In both the European Union and the United States results from such overloaded animals are normally not considered in hazard identification and risk assessment [34,35]. Lower lung burdens of kaolin RCF than those occurring in the rat RCC studies have been shown to cause overload [36] and therefore the results from these studies should not be used in formulating regulation. More importantly a new sample of kaolin RCF was prepared by Manville and this did not produce overload. It was shown that the overload produced by the original samples was due to its content of non-fibrous dust [37]. The second sample of RCF was more strictly comparable to the MMVF samples used at RCC therefore the results of the RCC inhalation results may not show that there are materials property differences between RCF and other wools but that samples prepared at Unifrax were positive and those from Manville negative. What ever its cause overload was not recognised earlier due to a misinterpretation of the pattern of fibre accumulation and to the assumption that 30mg.m -3 was the maximum tolerated dose for all the fibrous dusts tested. All these exposures have been called MTD studies but since the different dusts produced very different lung doses [30] it is difficult to see how one value could be the MTD in two species for so many dusts. Indeed it has been shown that the MTD was exceeded in rats even for the less bioaccumulative MMMVF10 [38], The larger lung burdens of RCF must have caused overload and all the pathology seen could be due to this and not to fibre exposure. A study with the same glasses in hamsters [39] also shows that in the original hamster study the MTD must also have been exceeded. When the same dusts were tested by IP injection there were interesting differences in the comparative activity of different fibres. Miller et al. [40] used some of the RCC samples in an IP study and found that the order of potencies found by inhalation testing were not repeated. In particular rockwool produced more tumours, and these occurred earlier, than did RCF. RCF4 containing 28% crystalline silica produced no tumours at all (Table one). Other IP studies [41,42] have produced similar results with rockwool being more, or equally, potent as RCF. MMVF21 rockwool is slightly more biopersistent than RCF. In one study long RCF fibres had a clearance half time of 55 days while rockwool gave half lives of 67 and 99 days when tested twice [43] other studies are consistent with this observation. IP injection tests are far more consistent with this observation than are the original RCC results.

7 Fibre type Kaolin RCF (RCF1) Rockwool (MMVF21) Zirconia RCF (RCF2) After use RCF (RCF4) Glass wool (MMVF10) Number of animals Number of mesotheliomas % mesothelioma Median survival (days) of mesothelioma cases Table 1 Partial Results of an intraperitoneal study [39] all rats were injected with 10 9 WHO fibres, Conclusion In Europe the inhalation results have resulted in the insulation wools including rockwool being classified as a category three carcinogen. RCF are category two with very rigorous, and increasing, legal controls. RCF may not be sold to the general public and under the present proposal for a new chemical policy could be banned except in authorised applications. The RCC experiments are confounded by overload and both IP and biopersistence studies suggest that RCF are no more hazardous than rockwool therefore the EU classification scheme leading to the present classification is flawed. Either RCF are treated too harshly or rockwool too lightly. Sales of rockwool have largely shifted to a less persistent composition but if the older rockwool is under classified then the millions of buildings insulated with this material must pose some risk especially when maintenance or demolition takes place. In any case the composition forming a boundary between European categories 2 and 3 has no foundation in evidence. While we have a great deal of data we still have gaps in our knowledge that must prevent us being entirely confident when devising fibre classification schemes. We all seek to enable the advantages of fibres, such as energy saving, to be exploited while avoiding any health risks. For example we cannot be certain what importance should be attached to the hamster results since too few fibres have been tested in this species. Similarly low particulate RCFs have not been tested in lifetime carcinogenicity assays and neither have particle contaminated glass wools. It seems that at this time an assumption justified by all the data and

8 conservative is that all fibres of equal length when present in the lung are equally active. Therefore for humans any risk is proportional to the magnitude of exposure and the persistence of the material in the lung; together these determine tissue dose and hence and likelihood of any health effect. References [1] International Agency for Research on Cancer (IARC). (1988). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Volume 43, Man-Made Mineral Fibers and Radon. International Agency for Research on Cancer, Lyon, France. [2] International Agency for Research on Cancer (IARC). (2002). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Volume 81, Man-Made Vitreous Fibres. Lyon, France. [3] Whorf B.L. (1956): Language, Thought and Reality (ed. J. B. Carroll). Cambridge, MA: MIT Press [4] European Directive 97/68/EEC [5] Alexander IC and Jubb GA. (1997). Development of a soluble high-temperature insulation fibre. Glastech Ber. 70: [6] Maxim LD, Mast RW, Utell MJ, Yu CP, Boymel PM, Zoitos BK, Cason JE (1999)Hazard assessment and risk analysis of two new synthetic vitreous fibers Regul Toxicol Pharmacol 1999; 30(1):54-74 [7]Lockey, J. E., LeMasters, G. K., Levin, L., Rice, C., Yiin, J., Reutman, S., and Papes, D. (2002). A longitudinal study of chest radiographic changes of workers in the refractory ceramic fiber industry. CHEST. 121: [8] Lockey, J. E., Levin, L., LeMasters, G. K., McKay, R. T., Rice, C. H., Hansen, K. R., Papes, D. M., Simpson, S., and Medvedovic, M. (1998). Longitudinal estimates of pulmonary function in refractory ceramic fiber manufacturing workers. Am. J. Respir. Crit. Care Med. 157: [9] Trethowan, W. N., Burge, P. S., Rossiter, C. E., Harrington, J. M., and Calvert, I. A. (1995). Study of the respiratory health of employees in seven European plants that manufacture ceramic fibers. Occup. Environ. Med [10] Cowie, H. A., Wild, P., Beck, J., Auburtin, G., Piekarski C., Massin, N., Cherrie, J. W., Hurley, J. F., Miller, B. G., Groat, S., and Soutar, C. A. (2001). An epidemiological study of the respiratory health of workers in the European refractory ceramic fibre (RCF) industry. Occup. Environ. Med. 58: [11] Mast, R. W., McConnell, E. E., Anderson, R., Chevalier, J., Kotin, P., Bernstein, D. M., Thévenaz, P., Glass, L. R., Miiller, W. C., and Hesterberg, T. W. (1995). Studies on the chronic toxicity (inhalation) of four types of refractory ceramic fiber in male Fischer 344 rats. Inhal. Toxicol. 7: [12] Mast, R. W., McConnell, E. E., Hesterberg, T. W., Chevalier, J., Kotin, P., Thévenaz, P., Bernstein, D. M., Glass, L. R., Miiller, W., and Anderson, R. (1995). Multiple dose chronic inhalation study of size-separated kaolin refractory fiber in male Fischer 344 rats. Inhal. Toxicol. 7: [13] McConnell, E. E., Mast, R. W., Hesterberg, T. W., Chevalier, J., Kotin, P., Bernstein, D. M., Thévenaz, P., Glass, L. R., and Anderson, R. (1995). Chronic inhalation toxicity of a kaolin-based refractory ceramic fiber in Syrian golden hamsters. Inhal. Toxicol. 7:

9 [14] Bellmann, B., Muhle, H., Ernst, H., Pohlmann, G., Sébastien, P., and Brown, R. C. (2002) Subchronic studies on man-made vitreous fibres: Kinetics of inhaled particles. Annals Occup. Hyg. 46(S1): [15] Brown, R. C., Bellmann, B., Muhle, H., Ernst, H., Pohlmann, G., and Sébastien, P. (2002). Subchronic studies on man-made vitreous fibres: Toxicity results. Annals Occup. Hyg. 46(1): [16] Bellmann, B., Muhle, H., Creutzenberg, O., Ernst H., Brown, R. C., and Sébastien, P. (2001). Effects of nonfibrous particles on ceramic fiber (RCF 1) toxicity in rats. Inhal. Toxicol. 13: [17] Moolgavkar, S. H., Luebeck, E. G., Turim, J., and Hanna, L. (1999). Quantitative assessment of the risk of lung cancer associated with occupational exposure to refractory ceramic fibers. Risk Anal. 19: [18] Moolgavkar, S. H., Luebeck, E. G., Turim, J., and Brown, R. C. (2000). Lung cancer risk associated with exposure to man-made fibers. Drug and Chemical Toxicol. 23(1): [19] Turim, J., Brown, R. C. (2003) A dose response model for refractory ceramic fibers. Inhal. Toxicol. in press. [20] Maxim, L. D., Allshouse, J. N., Chen, S. H., Treadway, J. C., Venturin, D. E. (2000). Workplace monitoring of refractory ceramic fiber in the United States. Regul. Toxicol. Pharmacol. 32: [21] Maxim, L. D., Allshouse, J. N., Deadman, J., Kleck, C., Kostka, M., Webster, D., Class, P., Sébastien, P. (1998). CARE: A European programme for monitoring and reducing refractory ceramic fibre dust at the workplace: initial results. Gefahrstoffe - Reinhaltunz der Luft. 58: [22] LeMasters, G. K., Lockey, J. E., Levin, L. S., McKay, R. T., Rice, C. H., Horvath, E. P., Papes, D. M., Lu, J. W., and Feldman, D. J. (1998). An industry-wide pulmonary study of men and women manufacturing refractory ceramic fibers. Am. J. Epidemiol. 148: [23] Hansen EF, Rasmussen FV, Hardt F, Kamstrup O (1999) Lung function and respiratory health of long-term fiber-exposed stonewool factory workers Am J Respir Crit Care Med 1999; 160(2): [24] Rossiter CE, Gilson JC, Sheers G, Thomas HF, Trenthowan WN, Cherrie JW, Harrington (1994) Refractory ceramic fibre production workers; analysis of radiograph readings Ann Occup Hyg 1994; 38(Suppl 1): [25] LeMasters, G. K., Lockey, J. E., Yiin, J. H., Hilbert, T. J., Levin, L. S., and Rice, C. H. (2003). Mortality of workers occupationally exposed to refractory ceramic fibers. J. Occup. Environ. Med. 45: [26] Walker AM, Maxim LD and Utell M. (2002). Risk analysis for mortality from respiratory tumors in a cohort of refractory ceramic fiber workers. Regul Toxicol Pharmacol 35: [27] Gross. P. Westrick M.L. Schrenk, H.H. & McNerney J.M.(1956) The effects of synthetic ceramic fiber dust upon the lungs of rats. AMA Archives of Industrial Health [28] Davis JMG, Addison J, Bolton RE, Donaldson K, Jones AD, Wright A. (1984).The Pathogenic Effects of Fibrous Ceramic Material; Aluminium Silicate Glass; Administered to Rats by Inhalation and Peritoneal Injection. In: "Biological Effects Of Man- Made Mineral Fibres". Proceedings of a WHO/IARC Conference, Copenhagen, April 20 to 22, Volume 2, pp [29] Smith DM, Ortiz LW, Archuleta RF, Johnson NF. (1987) ; Long-term health effects in hamsters and rats exposed chronically to man-made vitreous fibres. Ann Occup Hyg 32:

10 [30] Hesterberg T. W., and Hart, G. A. (2001) Synthetic vitreous fibers: a review of toxicology research and its impact on hazard classification. Crit. Rev. Toxicol. 31:1-53. [31] Mast, R. W., Yu, C. P., Oberdörster, G., McConnell, E. E, and Utell, M. J. (2000). A retrospective review of the carcinogenicity of refractory ceramic fiber in two chronic Fischer 344 rat inhalation studies: An assessment of the MTD and implications for risk assessment. Inhal Toxicol. 12: [32].Stanton MF, Layard M, Tegeris A, Miller E, Kent E. [1977] Carcinogenicity of Fibrous Glass: Pleural Response in the Rat in Relation to Fibre Dimension. J Nat Cancer Inst; 58: [33] Burdett G.J. Firth J.G. Rood A.P. & Streeter R.R. [1988] Application of fibre retention and carcinogenic curves to fibre size distributions of asbestos Ann Occup Hyg [34] Annex VI of the General Classification and Labeling Requirements for Dangerous Substances and Preparations. Available at [35] Presidential/Congressional Commission on Risk Assessment and Risk Management. (1997). Available at < rpt/rr6me001.htm>. [36] Creutzenberg, O., Bellman, B., and Muhle, H. (1997). Biopersistence and bronchoalveolar lavage investigations in rats after subacute inhalation of various man-made mineral fibres. Ann. Occup. Hyg. 41(S1): [37] Bellmann, B., Muhle, H., Creutzenberg, O., Ernst H., Brown, R. C., and Sébastien, P. (2001). Effects of nonfibrous particles on ceramic fiber (RCF 1) toxicity in rats. Inhal. Toxicol. 13: [38] Tran C.L, Jones A.D., Donaldson K. (1996) Evidence of overload, dissolution and breakage of MMVF10 fibers in the RCC chronic inhalation study Exp Toxicol Pathol 1996; [39] Hesterberg TW, Axten C, McConnell EE, Hart GA, Miiller W, Chevalier J, Everitt J, Thevenaz P, Oberdorster G 1999 Studies on the inhalation toxicology of two fiberglasses and amosite asbestos in the syrian golden hamster Part I. Results of a subchronic study and dose selection for a chronic study Inhal Toxicol; 11: [40] Miller BG, Searl A, Davis JMG, Donaldson K, Cullen RT, Bolton RE, Buchanan D, Soutar CA (1999) Influence of fiber length, dissolution and biopersistence on the production of mesothelioma in the rat peritoneal cavity Ann Occup Hyg ; 43: [41] Wardenbach P. Pott F and Wotowitz H-J, (2000) Differences between the classification of man-made vitreous fibres (MMVF) according to the European directive and German legislation: analysis of scientific data and implications for worker protection Eur.J.Oncol. 5(suppl.2), [42] Adachi S, Kawamura K, Takemoto K (2001) A trial on the quantitative risk assessment of man-made mineral fibers by the rat intraperitoneal administration assay using the JFM standard fibrous samples. Ind Health;39: [43] Hesterberg TW, Chase G, Axten C, Miller WC, Musselman RP, Kamstrup O, Hadley J, Morscheidt C, Bernstein D, Thevenaz P (1998) Biopersistence of synthetic vitreous fibers and amosite asbestos in the rat lung following inhalation Toxicol Appl Pharmacol; 151: