Lunge, Umwelt, Arbeitsmedizin. Linz, H. Greim Technische Universität München

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1 Lunge, Umwelt, Arbeitsmedizin Linz, H. Greim Technische Universität München Medizinisch toxikologische Problematik durch künstliche Mineralfasern

2 SCOEL: General OEL for MMMF Considering the uncertainties to extrapolate from LOEL to NOEL, the uncertainties of interspecies-extrapolation and possible intrinsic differences in fibre toxicity the conservative assessment factors of 20, and 10, respectively have been applied. The resulting values range between 1.3 and 3. Based upon this information the lowest value of 1.3 fibres/ml for glass wool fibres is adjusted to a general OEL of 1 fibre/ml. The OEL is applicable to man made mineral fibres without indication of carcinogenicity (see Annex I) and the characteristics: length >5 µm, diameter D <3 µm and a ratio L:D >3:1 (WHO fibres). For the fibres listed in the Table for which NOELs can be derived SCOEL will propose specific OELs.

3 NOELs and levels of MMMF by applying AF according to DECOS (1995) Fibres MMVF10 Rat, 24 mo MMVF10 Rat, 78 w MMVF10.1 Hamst, 13 w MMVF11 Rat, 24 mo MMMF21 Rat, 104 w MMMF22 Rat, 104 w X607 Rat, 24 mo NOEL Resp. f/ml Value derived by AF f/ml AF (LOEL) 25 LOEL) * * (LOEL) 10 20* * AF 20 because of LOEL

4 All inorganic with critical dimensions are suspected of having a carcinogenic potential and are classified as category 3 carcinogens. This is not applied if it can be shown that the fibre fulfils one of the following conditions (Nota Q): a short-term biopersistence test by inhalation showing that the longer than 20 µm fibres have a weighted half-life of less than 10 days; or a short-term biopersistence test by intratracheal instillation showing that the longer than 20 µm have a weighted half-life of less than 40 days; or an appropriate intraperitoneal test showing no evidence of excess carcinogenicity; or absence of relevant pathogenicity or neoplastic changes in a suitable long-term inhalation test.

5 SCOEL Refractory Ceramic fibres Data base: In rodent inhalation studies lung tumours Inflammation is the mechanism of carcinogenesis In epidemiological studies no increased rates in lung tumours, mesotheliomas, pleural plaques Since about 20 years (1990) workplace concentrations below 0.5 fibres/ml no effects on pulmonary function Conclusion of SCOEL Avoidance of inflammation prevents carcinogenicity Group C, OEL 0.3 f/ml

6 SCOEL Ableitung des OELs für RCF The average cumulative exposure among all workers in the > 60 f-mo/ml group was f-mo/ml, and When sorted by chronological age, those workers at age 60 in the > 60 f-mo/ml group experienced an average cumulative exposure of f-mo/ml. Assuming a 45 years exposure the average cumulative exposures of and f-mo/ml, respectively, result in an average fibre concentrations of 0.27 and 0.34 f/ml. Considering these values as no observed adverse effect levels SCOEL proposes an OEL of 0.3 f/ml.

7 Classification of Carcinogens and Risk Evaluation (Concept adopted by SCOEL - see Archives of Toxicology 82: 61-64, 2008) Chemical carcinogen, in humans and/or experimental animals Genotoxic DNA reactive, causing mutations Non-genotoxic Genotoxicity only on chromosome level (e.g. spindle, topoisomerase) Clearly DNA-reactive & initiating Borderline cases Weak genotoxin, secondary mechanisms important A: No threshold, LNT model to apply B: Situation not clear LNT as default C: Practical/apparent threshold likely D: Perfect/statistical threshold likely Numerical risk assessment, risk management NOAEL health-based exposure limits

8 Pathogenic sequence of effects of granular biopersistent particles or fibres Particle exposure Macrophage activation Inflammation impaired clearance Particle accumulation Oxidative stress DNA-adducts, mutations Metaplasia Fibrosis Cell proliferation (hyperplasia) Chronic inflammation Modified from P. Borm Tumours

9 Vorgehen nicht akzeptiert von BAuA in D Keine Wirkungsschwelle für Fasern akzeptiert Ableitung des Risikos anhand des Asbest-Risikos Bei Inhalation ist Ratte weniger empfindlich als Mensch Vergleichende i.p. Studien an Ratten werden als relevant angesehen. Die relative Wirkungsstärke von Fasern kann anhand i.p. Studien abgeschätzt werden. Für 1 RCF f/ml ergibt sich ein Krebsririko von 1:10

10 Argumentation aus verschiedenen Gründen fraglich Asbest Risiko: Selbst die EPA empfiehlt Reevaluierung Geringere Empfindlichkeit der Ratte bei Inhalation international nicht anerkannt. Abschätzung des Krebsrisikos aus Inhalationsstudien für 1 RCF F/ml: Pott/Roller (i.tr.) ~ 1 : 10 DECOS ~ 1 : 1000 Moolgavkar et al 2001 ~ 1 : Fayerweather et al 2002 ~ 1 : 1000

11 MAK Kommission diskutiert kritische Punkte 1.Fasern interferieren mit der Spindel des Zellkerns 2.Gilt das Prinzip Fasern? Kann der für inerte Partikel akzeptierte indirekt genotoxische Wirkungsmechanismus auf Fasern angewendet werden? Argument: Intratracheal oder intraperitoneal appliziert induzieren Fasern Mesotheliome, Partikel nicht.

12 Genotoxicity: Interaction with spindle apparatus Kirsch-Volders et al: Mutation Res. 464:3-11, 2000 Madle et al: Mutation Res. 464: , 2000 Pratt & Barron: Toxicol. Lett. 140/141: 53-62, 2003 The clearest argument for thresholds for heritable damage is for non DNA-reactive chemicals. This would include chemicals that are genotoxic via interaction with spindle, such as aneugens, since inactivation of the spindle is a multi-hit, multi-target event. MAK-Experten: Interaktion von Fasern mit der Spindel hemmt die Mitose und führt zum Zelltod.

13 Donaldson et al 2010: Mechanisms shared by both asbestos and long MWCNT 1. Failure of long fibres to negotiate the diaphragmatic stomata with subsequent retention of the long fibre dose at the diaphragm; this contrasts with smaller particles which easily leave the peritoneal cavity through the diaphragmatic stomata to accumulate in the parathymic nodes, 2.At the point where the long fibre dose accumulates at the peritoneal face of the diaphragm macrophages attempt to phagocytose the long fibres; they then undergo frustrated phagocytosis stimulating inflammation and mesothelial cell damage, leading to chronic inflammation and granuloma development. Donaldson et al, Particle and Fibre Toxicology 2010, 7:5

14 Murphy et al (Am J Pathol 2011, 178: ) The data confirm the hypothesis that although a proportion of all deposited particles passes through the pleura, the pathogenicity of long carbon nanotubes and other fibres arises as a result of lengthdependent retention at the stomata on the parietal pleura.

15 Pl. parietalis Pl. visceralis Donaldson et al 2010

16 Donaldson 2010 Ø ca 3 µm

17 The frustrated phagocytosis paradigm as it relates to long and short fibres of asbestos (left) and various forms of carbon nanotubes (right). Donaldson et al 2010

18 Das Prinzip Fasern? Asbest wie auch biopersistente Fasern erreichen die Pleura und induzieren zumindest theoretisch Mesotheliome, aber Die US Kohorte von 1085 RCF Exponierten (LeMasters et al) zeigt keine Mesotheliome, zwei unklare pleurale Plaques. Hebt die Epidemiologie den Verdacht auf? Frage ausreichender Latenzzeit: 19% der Arbeiter mehr als 20 Jahre exponiert 46% der Arbeiter über mehr als 20 Jahre überprüft Seit 1990 Arbeitsplatzkonzentration unter 0,5 f/ml.

19 Zusammenfassung Die beobachtete Genotoxizität von Fasern kann als sekundär angesehen werden und lässt sich auf die Bildung reaktiver Sauerstoffspezies zurückführen. Die Interaktion mit dem Spindelapparat hat keine genotoxischen Konsequenzen. Für nicht biobeständige Fasern lässt sich ein NOEL festlegen. Auch für biobeständige Fasern lässt sich aufgrund des sekundären genotoxischen Mechanismus für die Effekte auf die Lunge ein NOEL festlegen. Offen ist die Frage eines NOEL für Mesotheliome bei biobeständigen Fasern.

20 Ken Donaldson*, Fiona A Murphy, Rodger Duffin, Craig A Poland Asbestos, carbon nanotubes and the pleural mesothelium: a review of the hypothesis regarding the role of long fibre retention in the parietal pleura, inflammation and mesothelioma. Particle and Fibre Toxicology 2010, 7:5

21 Ken Donaldson et al 2010 Diagramm illustrating a pathogenic fibre according to the pathogenic paradigm and the role of particle characteristis

22 Hypothesised sequence of events leading to pleural responses as a consequence of long fibre retention at the parietal pleural stomatal openings (Donaldson et al 2010)

23 Classification of a fibre into the various categories is made according to the following criteria: (Annex II to Council Directive 67/548/EEC): Category 1, known to be carcinogenic to man Positive results from epidemiological studies Category 2, should be regarded as if they are carcinogenic to man Positive results from animal studies Category 3, cause concern for man owing to possible carcinogenic effects, but in respect of which the available information is not adequate for making a satisfactory assessment Classification based primarily on animal results