The Necessity of Developing New Criteria for Carcinogen Classification of Fibers by the Mak Commission

Abstract

The criteria for carcinogen classification of critical man-made mineral fibers (MMMF) by the MAK Commission are presently based on carcinogenicity and genotoxicity data. This classification is based on qualitative criteria. The MAK Commission considers all inorganic fibers and fibrous dust particles with a ratio of length to diameter greater than 3:1 and that are longer than 5 µm and have a diameter less than 3 µm to be potential carcinogens (category 3) (DFG, 1998; Creim, 1997). For chemicals in general, the MAK Commission has supplemented the three previously used categories “carcinogenic to humans,” “carcinogenic to animals,” and “suspected of having carcinogenic potential” with two additional categories. Chemicals that act primarily by nongenotoxic mechanisms and for which evaluation of low-dose exposure is possible are classified in category 4. Cenotoxic carcinogens for which risk at low doses can be assessed are classified in category 5. The essential feature of these two categories is that exposure at the workplace up to a given limit (MAK value) does not contribute significantly to the risk of cancer in humans. Thus, for classification of fibers into category 4 or 5, the evaluation of primary or secondary genotoxic effects is required. For the establishment of an MAK value for fibers, the identification of a no-observed-effect level (NOFL) representing a steady state of fiber uptake and elimination is necessary. Early inflammatory responses associated with changes in the parameters of bronchoalveolar lavage and cell proliferation in lung tissue are considered sensitive parameters for identifying the NOEL. Data on biopersistence under exposure conditions that prevent particle accumulation exceeding the steady-state conditions of the NOEL are required in order to consider the potential of fiber accumulation as an inherent fiber property including fiber dissolution and fiber disintegration. It is therefore necessary that the design of testing strategies to evaluate toxicity and carcinogenicity of fibers include dose-response studies to identify the NOEL of the most sensitive endpoint, such as by analysis of parameters of lung lavage, histopathol-ogy, and determination of biopersistence. Further, a basic understanding of the underlying genotoxic mechanisms is required for differentiation between primary and secondary mechanisms and their dose dependence.