Expert workshop on the hazards and risks of poorly soluble low toxicity particles

Abstract

‘Lung particle overload’ refers to the impaired lung particle clearance and increased particle retention occurring with high lung doses of poorly soluble low toxicity (PSLT) particles. In rats, lung particle overload is associated with inflammation, epithelial hyperplasia, and, in extreme cases, lung cancer. While the human relevance of rat lung tumors occurring under overload has been questioned, recent regulatory decisions have considered these outcomes evidence of possible human hazard. To better understand the state-of-the-science on PSLT toxicology, an Expert Workshop was held to document agreements and differences amongst a panel of highly experienced scientists and regulators. Key outcomes included: a functional definition of PSLTs; agreement the rat is a sensitive model for PSLT inhalation toxicology; identifying lung inflammation as a critical endpoint for PSLT risk assessment; and, agreement rat lung cancer occurring only under conditions of lung particle overload does not imply a cancer hazard for humans under non-overloading exposures. Moreover, when asked – should PSLTs be considered as human lung carcinogens based on rat data alone (and no supporting data from other species), the expert consensus was: ‘No. However, the experts noted the current default regulatory position on rat lung overload data alone would be the suspicion of human carcinogen hazard.’ The many areas of the expert agreement provide guidance for design, interpretation, and extrapolating PSLT inhalation toxicology studies. Considering the workshop outcomes, the authors recommend guidelines for evaluation and classification of PSLT be reassessed; and, prior decisions on PSLT hazard classification be revisited to determine if they remain appropriate.

Keywords:

• PSLT
• particles
• lung particle overload
• hazard
• risk
• lung cancer
• inhalation

Acknowledgments

All opinions, critical data reviews, and conclusions in this review are the authors own and were not influenced or contributed to by the sponsors. This article clearly discriminates between expert opinions and authors interpretation

Disclosure statement

The authors have no competing interests although both engage in consulting activities, none of these have a conflict of interest with the current subject. PB has been involved in consulting for Vliegasunie and IMA. Both have published several original papers and reviews on the PSLT and lung particle overload subject matter in the previous academic (P.B.) or academic and corporate (K.D.) settings.

Availability of data and material

The authors have the sole responsibility for retrieval, selection and interpretation and writing of the manuscript.

Additional information

Funding

The organization of the meeting was supported in-kind by the University of Edinburgh and the IOM and we acknowledge the contributions of Dr. Rodger Duffin and Dr. Lang Tran in organizing and hosting the meeting. The costs for the organization including travel for experts were carried by sponsorships from the International Carbon Black Association (ICBA), The TDMA, Eurometaux, International Antimony Association; IMA, Vliegasunie, and the Iron Platform. The organization was handled by Nanoconsult and Healthcare Innovation Partners.