The hazards and risks of inhaled poorly soluble particles - where do we stand after 30 years of research?

BACKGROUND: In 2006, titanium dioxide and carbon black were classified by IARC as "possibly carcinogenic to humans" and in 2017 the European Chemicals Agency's (ECHA) Committee for Risk Assessment concluded titanium dioxide meets the criteria to be classified as suspected of causing cancer (category 2, through the inhalation route). These classifications were based primarily on the occurrence of lung cancer in rats exposed chronically to high concentrations of these materials, as no such responses have been observed in other animal species similarly exposed. After the EU classification of titanium dioxide, it was suggested that Poorly Soluble particles of Low Toxicity (PSLTs) can be evaluated as a group. MAIN BODY: To better understand the current state of scientific opinion, we sought perspective from several international experts on topics relevant to the classification of carbon black; titanium dioxide; and, the potential future classification of PSLTs. Areas discussed included: grouping of PSLTs; the relevance of rat lung cancer responses to high concentrations of PSLTs; and, clearance overload and implications for interpretation of inhalation toxicology studies. We found there were several areas where a large majority of experts, including ourselves, agreed. These included concerns on the grouping of PSLT and the definition of clearance overload. Regarding the extrapolation of PSLT associated lung cancer in rats there were some strongly held differences, although most experts questioned the relevance when excessive exposures which overwhelm lung clearance were required. SHORT CONCLUSION: Given the ongoing discussion on PSLT classification and safety, we believe it is important to re-activate the public debate including experts and stakeholders. Such an open discussion would serve to formally document where scientific consensus and differences exist. This could form the basis for design of future safety programs and safety assessments.

The role of black carbon as a catalyst for environmental redox transformation.

Black carbon (BC) is an important class of geosorbents that control the fate and transport of organic pollutants in soil and sediment. We previously demonstrated a new role of BC as an electron transfer mediator in the abiotic reduction of nitroaromatic and nitramine compounds by Oh and Chiu (Environ Sci Technol 43:6983-6988, 2009). We proposed that BC can catalyze the reduction of nitro compounds because it contains microscopic graphitic (graphene) domains, which facilitate both sorption and electron transfer. In this study, we assessed the ability of different types of BC--graphite, activated carbon, and diesel soot--to mediate the reduction of 2,4-dinitrotoluene (DNT) and 2,4-dibromophenol (DBP) by H(2)S. All three types of BC enhanced DNT and DBP reduction. H(2)S supported BC-mediated reduction, as was observed previously with a thiol reductant. The results suggest that BC may influence the fate of organic pollutants in reducing subsurface environments through redox transformation in addition to sorption.

Water interaction with hydrophobic and hydrophilic soot particles.

The interaction of water with laboratory soots possessing a range of properties relevant for atmospheric studies is examined by two complementary methods: gravimetrical measurement of water uptake coupled with chemical composition and porosity analysis and HTDMA (humidified tandem differential mobility analyzer) inference of water uptake accompanied by separate TEM (transmission electron microscopy) analysis of single particles. The first method clarifies the mechanism of water uptake for bulk soot and allows the classification of soot with respect to its hygroscopicity. The second method highlights the dependence of the soot aerosol growth factor on relative humidity (RH) for quasi-monodisperse particles. Hydrophobic and hydrophilic soot are qualitatively defined by their water uptake and surface polarity: laboratory soot particles are thus classified from very hydrophobic to very hydrophilic. Thermal soot particles produced from natural gas combustion are classified as hydrophobic with a surface of low polarity since water is found to cover only half of the surface. Graphitized thermal soot particles are proposed for comparison as extremely hydrophobic and of very low surface polarity. Soot particles produced from laboratory flame of TC1 aviation kerosene are less hydrophobic, with their entire surface being available for statistical monolayer water coverage at RH approximately 10%. Porosity measurements suggest that, initially, much of this surface water resides within micropores. Consequently, the growth factor increase of these particles to 1.07 at RH > 80% is attributed to irreversible swelling that accompanies water uptake. Hysteresis of adsorption/desorption cycles strongly supports this conclusion. In contrast, aircraft engine soot, produced from burning TC1 kerosene in a gas turbine engine combustor, has an extremely hydrophilic surface of high polarity. Due to the presence of water soluble organic and inorganic material it can be covered by many water layers even below water saturation conditions. This soot demonstrates a gradual diameter growth factor (D(wet)/D(dry)) increase up to 1.22 at 93% relative humidity, most likely due to the presence of single particles with water soluble material heterogeneously distributed over their surface.

Use of mechanistic data in IARC evaluations.

Consideration of mechanistic data has the potential to improve the analysis of both epidemiologic studies and cancer bioassays. IARC has a classification system in which mechanistic data can play a pivotal role. Since 1991, IARC has allowed an agent to be classified as carcinogenic to humans (Group 1) when there is less than sufficient evidence in humans but there is sufficient evidence in experimental animals and "strong evidence in exposed humans that the agent acts through a relevant mechanism of carcinogenicity." Mechanistic evidence can also substitute for conventional cancer bioassays when there is less than sufficient evidence in experimental animals, just as mechanistic evidence can substitute for conventional epidemiologic studies when there is less than sufficient evidence in humans. The IARC Monographs have used mechanistic data to raise or lower a classification that would be otherwise based on epidemiologic studies and cancer bioassays only. Recently, the IARC Monographs have evaluated several agents where mechanistic data were pivotal to the overall evaluation: benzo[a]pyrene, carbon black and other poorly soluble particles, ingested nitrates and nitrites, and microcystin-LR. In evaluating mechanistic data, it is important to consider alternative mechanistic hypotheses, because an agent may induce tumors through multiple mechanisms.