No inflammatory effects after acute inhalation of barium sulfate particles in human volunteers

Abstract

Background Most threshold limit values are based on animal experiments. Often, the question remains whether these data reflect the situation in humans. As part of a series of investigations in our exposure lab, this study investigates whether the results on the inflammatory effects of particles that have been demonstrated in animal models can be confirmed in acute inhalation studies in humans. Such studies have not been conducted so far for barium sulfate particles (BaSO4), a substance with very low solubility and without known substance-specific toxicity. Previous inhalation studies with zinc oxide (ZnO), which has a substance-specific toxicity, have shown local and systemic inflammatory respones. The design of these human ZnO inhalation studies was adopted for BaSO4 to compare the effects of particles with known inflammatory activity and supposedly inert particles. For further comparison, in vitro investigations on inflammatory processes were carried out. Methods Sixteen healthy volunteers were exposed to filtered air and BaSO4 particles (4.0 mg/m3) for two hours including one hour of ergometric cycling at moderate workload. Effect parameters were clinical signs, body temperature, and inflammatory markers in blood and induced sputum. In addition, particle-induced in vitro-chemotaxis of BaSO4 was investigated with regard to mode of action and differences between in vivo and in vitro effects. Results No local or systemic clinical signs were observed after acute BaSO4 inhalation and, in contrast to our previous human exposure studies with ZnO, no elevated values of biomarkers of inflammation were measured after the challenge. The in vitro chemotaxis induced by BaSO4 particles was minimal and 15-fold lower compared to ZnO. Conclusion The results of this study indicate that BaSO4 as a representative of granular biopersistent particles without specific toxicity does not induce inflammatory effects in humans after acute inhalation. Moreover, the in vitro data fit in with these in vivo results. Despite the careful and complex investigations, limitations must be admitted because the number of local effect parameters were limited and chronic toxicity could not be studied.

Systemic inflammatory effects of zinc oxide particles: is a re-evaluation of exposure limits needed?

“…Inhalation studies in humans with chemically inert particles are extremely sparse in the literature; thus, it was unknown whether the effects that were observed after ZnO inhalation were due to a physical particle effect or a substance-specific characteristic. Therefore, a further acute inhalation study with the chemically inert substance barium sulphate (BaSO 4 ) was conducted (Monsé et al 2022 ). We selected those effect parameters that had been shown to be sensitive for the detection of airway inflammation in our previous ZnO studies (Monsé et al 2018 , 2021 ).…”

Reply on the comments of Ulla Vogel and colleagues on their recently published paper entitled “Re-evaluation of the occupational exposure limit for ZnO is warranted. Comments on ‘Systemic inflammatory effects of zinc oxide particles: is a re-evaluation of exposure limits needed?’ by Christian Monsé et al.”

“…Zinc-specific mechanism of action: We did not define the causal mechanism of action clearly. In our considerations, we focused on the comparison of chemically inert particles with zinc oxide particles (see BaSO 4 study, Monsé et al 2022 ) and attributed the observable systemic inflammation to zinc ions. We agree that other metal oxides can also cause similar effects.…”