Comment on Beryllium Toxicity Papers

The comments challenging the conclusions on skin sensitizing properties of beryllium metal are very welcome and I consider this feedback important to stimulate a scientific discussion. It is important to highlight that the scope of the sensitization study conducted was to assess the skin sensitizing potential of beryllium metal, not of other beryllium species, in the context of a Registration, Evaluation and Authorisation of Chemicals (REACH) registration dossier. Registration in the context of REACH is substance-specific, and beryllium metal is handled separately from beryllium compounds in Europe [see Part 3 of Regulation (EC) 1272/2008, where separate Index Numbers are assigned to beryllium and beryllium compounds]. Exposure to soluble beryllium compounds in industrial settings in Europe is prevented by the commercial inavailability of these compounds and restriction of the industrial processes to melting, casting, and physical processing of metal and alloys. Based on the differences in physical, chemical, and toxicity characteristics between soluble beryllium compounds and insoluble beryllium metal, read across is not considered appropriate. The existing studies in the literature were not considered relevant as none of the studies demonstrate sensitivity after exposure to beryllium metal alone if no soluble compounds were used either to induce sensitivity or to challenge. The new skin sensitization study performed to obtain information on the metal alone was conducted with beryllium metal (under funding of the REACH Beryllium consortium, formed by four companies with equal share and rights to define their cooperation required by the REACH regulation). No conclusion on soluble compounds can be derived from the study results as this was outside the scope of this investigation. Regarding the criticism of the experimental approach, it should be noted that the assays were conducted in a regulatory environment under REACH, where animal experiments have to be avoided or at least minimized as far as possible. Conducting a non-adjuvant local lymph node assay (LLNA) or mouse ear swelling test (MEST) with extracts of the metal (with predictably very low concentrations), or suspensions (where the metal particles will be dislodged by grooming after drying), alone would unlikely be considered conservative enough by regulatory authorities to allow a decision for non-classification. The experimental approach chosen is (in agreement with the current international regulatory data requirements) considered conservative and to represent the worst case technically possible. Delivery of the metal is ensured by the intradermal injection of the suspension, and the immune system is stimulated with Freund’s adjuvant to provoke the induction of sensitivity. Exposure during dermal induction and challenging is mimicking realistic skin contact conditions as far as realizable under the experimental conditions and ionizing properties/pH of polyethylene glycol do not largely differ from petrolatum used as vehicle to induce animals with beryllium oxide (Tinkle et al., 2003). The concept of conducting parallel studies with the MEST and the LLNA is considered an interesting approach to investigate the sensitizing potential of mixed exposure to beryllium metal and compounds (which does not happen in any industrial environment in Europe) and to increase our knowledge on beryllium compounds. However, this is neither considered necessary for assessment of the sensitization potential of beryllium metal alone (which was conclusively investigated in the guinea pig maximization test) nor possible under REACH in the light of repetition of a vertebrate study.