Hazards associated with inhalation of airborne particles in occupational settings have received much attention over the last decades, and great progress has been achieved in efforts to better understand the mechanisms of action by which these substances may act in lung tissue. As well, much knowledge on the pertinent characteristics of airborne particles which bear relevance to biological action has been gained over the more recent years. Thus, various physico-chemical parameters of these materials such as dimensions and chemical composition have been more narrowly defined, and this has brought a better way to assess their relative potency in relation to some of these parameters to biological action.

Over the last two decades, the combination of advances in analytical techniques and a better definition of experimental protocols to test "respirable" particles for relative biological activity have allowed investigators to focus on one particular feature of inhaled particles with regard to their interaction with lung tissue. Thus, while it had long been shown that dose and dimensions surely have to be considered in assessing potency, it was discovered that there is yet another key property of inhaled mineral particles, related to their chemical makeup: durability in biological environment. This characteristic is often described as "biopersistence", which is related in part to its chemical composition.

It has been clearly demonstrated in numerous animal experiments and in several epidemiological surveys that adverse health effects are associated with particles which are "retained" (biopersistent) for long periods in the lung, rather than with those that are "cleared" rapidly. Today, there is a wide international consensus in recognizing the "three Ds" (dimensions, dose and durability) as the key parameters of biological pertinence in assessing the biological activity of respirable mineral fibers.

Still more recently, further research led to the recognition that with regard to durability (biopersistence), parts of the chemical makeup of mineral fibers seem to account closely for their relative biopersistence in acidic milieu of the lung, where "alkaline-rich" particles are less likely to be biopersistent. Thus, it appears that those fibers which display a low percentage (= 18%) of alkaline oxides may remain for rather long periods in the lung (they are biopersistent), whereas those having a higher percentage (= 18%) of alkaline oxides, such as NaO2, K2O, CaO, MgO, BaO) would be less biopersistent, i.e.: cleared more rapidly from the lung.

Classification
For many years, the classification of mineral fibers by the International Agency for Research on Cancer (IARC) included four main categories: group 1: carcinogenic to humans; group 2a: probably carcinogenic; group 2b: possibly carcinogenic; group 3: not classifiable as to its carcinogenicity to humans; group 4: probably not carcinogenic to humans.

More recently, following lengthy consultations with international experts, the European Union issued a "FIBER DIRECTIVE" for man-made mineral fibers classification. At the outset, the group of experts had a 9 box matrix, based on the so-called KNB index (sum total of alkaline oxides), together with fibre mean diameter, but the focus was condensed into the following 3 groups identified in the fibre Directive, namely:

• Continuous filament fibres with mean diameter less than 6 um: no classification for carcinogenicity;
• Fibres with mean diameter less than 6 um, and less than 18% alkaline oxides: "Category 2" carcinogens (probably carcinogenic)
• Fibres with mean diameter less than 6 um, and greater than 18% alkaline oxide: "Category 3" carcinogens (possibly carcinogenic)

Indeed, it is possible under the European Fibre Directive to "test out" of the classification as "category 3 carcinogen" for fibres with greater than 18% alkaline oxides on the basis of certain criteria laid down in the Directive, including absence of relevant pathogenicity and an absence of neoplastic change in an inhalation bioassay and demonstration of low biopersistence in a validated short term biopersistence test, using either inhalation or intratracheal administration of fibres.*

Fibrox Fibers
Recently, a representative sample of Fibrox 300 fibers has been submitted for elemental analysis by an independent laboratory. The results obtained show that the sum of alkaline oxides comes to 28.85%, significantly higher than the 18% cut-off indicated in the European Fiber Directive. The interpretation is therefore that this fiber is not category 2, but falls clearly into the lower carcinogen category 3. Furthermore, the relatively large diameter of Fibrox 300 milled fiber (5-6 microns by population; 8-9 microns by mass distribution) would place this fiber very close to the exclusion limit (= 6 microns) as set out in the Fibre Directive.

AEA Technology (Biosciences)
Harwell, Didcot U. K.

Pertinent bibliography

Bernstein, D.M. (1998), "The Scientific and Health Related Reasons for Fiber Classification by the EC", VDI Berichte 1417, pp. 111-128, 1998 published by the Verein Deutscher Ingenieure, VDI Verlag GmbH, Düsseldorf, 1998 (ISSN 0083-5560, ISBN 3-18-091417-3).

Bernstein, D.M. (1997a). Data Analysis of intratracheal and inhalation biopersistence data. Report to the European Commission, Directorate General - JRC, Institute for Health and Consumer Protection, Toxicology and Chemical Substances Unit.

Bernstein, D.M. (1997b). Correlation between short term biopersistence and chronic toxicity studies. Report to the European Commission, Directorate General - JRC, Institute for Health and Consumer Protection, Toxicology and Chemical Substances Unit.

Report EUR 18748 EN (1999) "Methods for the Determination of the Hazardous Properties for Human Health of Man Made Mineral Fibres (MMMF) ed. D. M. Bernstein & J.M. Riego Sintes. European Commission Directorate General - JRC, Institute for Health and Consumer Protection, Toxicology and Chemical Substances Unit

Brown, R.C., Pigott G.H. and Alexander I. (1995) Classification of MMMF. Ann. Occup. Hyg. 39 (2), 135-140 Commission Directive 97/69/EC, O.J. No. L 343, p. 19 - 24

Council Directive 67/548/EEC, O.J. No. L 196, p. 1.

EPA, Workshop Report on Chronic Inhalation Toxicity and Carcinogenicity Testing of Respirable Fibrous Particles, United States Environmental Protection Agency, Washington, DC, EPA-748-R-96-001, January 1996.

Guidelines for setting specific concentration limits for carcinogens in Annex I of Directive 67/548/EEC - Inclusion of potency considerations - Commission Working Group on the Classification and Labelling of Dangerous Substances. In press and also Website: http://europa.eu.int/comm/dg11/dansub/potency.pdf

Oberdorster G., Evaluation and use of animal models to assess mechanisms of fibre carcinogenicity. IARC Sci. Publ. 1996;(140):107-25.

* Currently, the EU has different criteria from the IARC ones and only 3 categories for hazardous subsances with possible carcinogenic properties:

• Cat. 1, R45 (+ symbol T (Toxic): may cause cancer (human evidence based on epidemiological studies).
• Cat. 2, R45(+ symbol T (Toxic) ): may cause cancer: positive data in two animal species; clear positive evidence in one species + supportive genotoxicity data or other ( metabolism, biochemistry, benign tumours)
• Cat. 3, R68 (+ symbol Xn (harmful): Limited evidence of carcinogenic effect: substances sufficiently studied but effect insufficient for classification in Cat 2, or substances inadequately studied but of concern for man = temporary classification.

• Back to the main Articles index.