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 askedshould 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. ARTICLE HISTORY

Lung retention and particokinetics of silver and gold nanoparticles in rats following subacute inhalation co-exposure

“…For Single AuNP exposure, a retention half-time (T 1/2 ) was 81.5 days, while co-exposure with AgNP reduced the AuNP T 1/2 to 54.2 days. Given that the retention half times for AuNPs for both scenarios -single and combined exposure -are within the range of normal physiological alveolar clearance rates of 60-90 days for poorly soluble particles in rats [21], a significant difference cannot be substantiated. Therefore, AuNP clearance was likely not influenced by the presence of AgNP co-exposure, which is also supported by the same retained fraction of Au in the lung at day 28 of both single and co-exposure.…”

Comment on Saber et al. (2019), “Commentary: the chronic inhalation study in rats for assessing lung cancer risk may be better than its reputation”

“…Unfortunately, in their Commentary, Saber et al [1] make several significant errors in their interpretation and representation of key studies which, when accurately considered, do not support the author's statements and conclusions on relationships between lung clearance and rat lung cancer; species differences; and the predictiveness of rat lung cancer for nanosized PSLT. Germane to this discussion are the outcomes of a recent workshop on inhaled PSLT where a panel of 15 experts on PSLT toxicology and regulatory matters reached consensus that "rat lung tumors occurring with PSLT only under lung particle overload are not relevant to humans under non-overload exposure conditions" [15].…”

Olivine Dissolution in Simulated Lung and Gastric Fluid as an Analog to the Behavior of Lunar Particulate Matter Inside the Human Respiratory and Gastrointestinal Systems

“…It should be noted that many of these previously mentioned studies extrapolate the toxicity results of rats to humans which may not translate to actual human toxicity due to rats being much more sensitive to biological stimuli than humans (Bos et al., 2019 ; Driscoll & Borm, 2020 ). The differences between rats and humans make it difficult to draw definitive conclusions regarding the toxicity of poorly soluble particulate matter (Driscoll & Borm, 2020 ).…”

“…It should be noted that many of these previously mentioned studies extrapolate the toxicity results of rats to humans which may not translate to actual human toxicity due to rats being much more sensitive to biological stimuli than humans (Bos et al., 2019 ; Driscoll & Borm, 2020 ). The differences between rats and humans make it difficult to draw definitive conclusions regarding the toxicity of poorly soluble particulate matter (Driscoll & Borm, 2020 ). Whether poorly soluble particles (PSP) should be considered carcinogenic or not, is dependent on both epidemiological data and studies involving other animals such as mice, hamsters, primates, etc (Driscoll & Borm, 2020 ).…”

“…The differences between rats and humans make it difficult to draw definitive conclusions regarding the toxicity of poorly soluble particulate matter (Driscoll & Borm, 2020 ). Whether poorly soluble particles (PSP) should be considered carcinogenic or not, is dependent on both epidemiological data and studies involving other animals such as mice, hamsters, primates, etc (Driscoll & Borm, 2020 ). For example, studies working with diesel and coal particulates show a significant portion of those particles trapped in the alveoli of rats but more or less evenly distributed between the alveoli and interstitium, which is the space between the alveolar epithelium and capillary endothelium, in monkeys (Nikula et al., 1997 ).…”