Why Nanoparticles pose health risks: mechanisms of action
Jacob Schor ND, FABNO
Jacob Schor ND, FABNO
At this point it is pretty much accepted that airborne exposure to environmental nanoparticles is associated with significant increases in morbidity and mortality, that is breathing air with little tiny particles in that it leads to sickness and earlier death. This is best proven in association with air pollutants from motor vehicle exhaust, in particular diesel exhaust. Yet at this point our understanding of why nanoproblems cause health problems is rudimentary at best.
A new study was recently published that will help to further our understanding of these mechanisms. In this study Miller et al ask and then answer a fundamental question; do nanoparticles translocate across the lung and cause cardiovascular disease directly or do they simply trigger systemic inflammatory reactions that in turn increase disease risk?
reference: Miller MR, Raftis JB, Langrish JP, et al. Inhaled nanoparticles accumulate at sites of vascular disease. ACS Nano 2017, 11,4542-4552.
The authors conducted a series of separate experiments, all investigating how nanoparticles might trigger acute cardiovascular events. In the first trial, 14 healthy male humans were exposed to gold nanoparticles by acute inhalation followed by blood and urine sampling to determine if particles translocated across the lung. In a follow up trial 19 healthy volunteers were exposed to either smaller (app. 4 nm) or slightly larger (34 nm) particles by inhalation and monitored through blood and urine testing for absorption. In a separate experiment, mice were exposed to gold nanoparticles varying in sizes from 5 nm to 200 nm and accumulation in blood and urine was determined. In a third human experiment, the carotid arteries of humans exposed to inhaled gold nanoparticles prior to surgery were excised and evaluated.
Most of these experiments were conducted on humans. The exception was an experiment in which mice were used, specifically apolipoprotein E knockout mice (ApoE-/-) who had been fed a high fat diet to accelerate development of atherosclerotic lesions. In the carotid experiment, the human participants were patients who had recently had cerebrovascular accidents and were scheduled to undergo carotid endarterectomy. Twelve patients were recruited of which three were exposed to gold nanoparticles (5 nm) for four hours under resting conditions 24 hours prior to surgery.
Gold nanoparticles were used in these studies because they are of similar size to combustion derived nanoparticles but have low biological activity. Their presence was also easier to measure. Endogenous levels of gold in the blood are low and it could be assumed that any detected material would have been derived experimentally. Levels of gold were determined using high-resolution inductively coupled plasma mass spectroscopy (HR-ICPMS) and Raman microscopy.
Results: Gold was detected in the blood of healthy volunteers exposed to inhaled nanoparticles within 15 minutes and was still present 3 months after exposure. Levels were significantly greater following inhalation of smaller (5 nm) particles compared to larger (30 nm) particles. In mice accumulation was markedly greater in the smaller (<10nm) particles than in the larger (10-200 nm) range. The gold nanoparticles preferentially accumulated in areas of greater inflammation, in particular vascular lesions. Inhaled gold nanoparticles rapidly translocate into systemic circulation and accumulate at sites of vascular inflammation. This provides a direct mechanism that explains the link between environmental nanoparticles and cardiovascular disease.
Though this study may strike some of our readers as a bit esoteric, it’s important that we pay attention to this whole nanoparticle business. Our exposure to nanoparticles is increasing quickly, both because of motor vehicle exhaust but also due the increased use of nanoparticles for industrial applications. We aren’t just breathing in these particles, we are eating them as food additives, rubbing them on our skin as cosmetics and swallowing them as pharmaceutical agents. Our exposure is increasing rapidly and we may inadvertently be increasing health risks.
In recent years various studies have reported significant associations between inhaled nanoparticle exposure derived from vehicular exhaust and morbidity and mortality risk. We now have a decent explanation why and how this happens. In addition the rapid growth of nanomaterial manufacture and utilization has the potential to greatly increase human exposure. Knowledge from this study may help us avert an accidental increase in morbidity by encouraging implementation of safe manufacturing and handling practices to reduce accidental exposures. Up until this time our understanding of a mechanism of action that would explain the cardiovascular disease association has been rudimentary.
This paper advances our understanding and suggests caution.
The authors demonstrated that inhaled nanoparticles translocate from the lung into the circulation in man, and the particles accumulate at sites of vascular inflammation. Particle translocation appears to be size dependent with greater translocation and accumulation of smaller nanoparticles.
It has already been demonstrated that acute exposure to diesel exhaust causes vascular dysfunction, thrombosis and myocardial ischemia in healthy individuals and in patients with coronary heart disease .  Chronic exposure to particulate air pollution is associated with development and progression of atherosclerosis in both animals and humans. It has not been clear how this happens. Inhaled particles are known to deposit deep in the lungs and trigger oxidative stress and inflammation.  One theory has been that the inflammatory mediators triggered by these particles pass into general circulation and influence disease risk. The alternative explanation has been that the nanoparticles themselves penetrate the alveolar epithelium and translocate into the circulation and directly contribute to disease. This paper strongly suggests that the later mechanism is more likely. It is probably not this simple a choice. In the end we will likely come to understand that the nanoparticles trigger tissue inflammation, which increases the translocation of particles. 
While this evidence provides a convincing explanation for how CVD risk may be linked to environmental nanoparticle exposure, it only hints toward a possible explanation for the results seen in Baker et al’s 2015 paper that positively associated air pollution levels to suicide rates in Salt Lake City  or the Power et al paper that found an association between air pollution levels and anxiety.  These two papers might suggest that nanoparticles not only pass into general circulation but that they also cross the blood brain barrier triggering psychological morbidities as well.
Some may insist that the evidence presented in this paper is not yet proof of a causative association; the nanoparticles may only accumulate at sites of vascular disease but they may not cause or aggravate the condition. To be fair this is true, yet at this point we should consider it likely only a matter of time until the final proof is published.
There are immediate clinical concerns raised by this and other recent papers. Of obvious concern are patients with or at risk for cardiovascular disease. Limiting exposure to obvious sources of inhaled nanoparticles, in particular diesel exhaust may have benefit in limiting disease progression. Less obvious are the risks posed by a growing number of nanoparticle exposures that are becoming more and more common in everyday life. One example that few would recognize as a CVD hazard are the toner inks used in home and office printing.
Titanium dioxide nanoparticles have also become ubiquitous in our lives and pose their own risks that few people are aware of. This paper brings further recognition to the problems posed be diesel and other fossil fuel combustion byproduct nanoparticles and alerts us to the danger posed by a wide variety of nano-substances considered benign, not because of their chemical constituents but because of their size.
below is a chart promoting all the great uses of nanoparticles…..
- Lucking AJ, Lundback M, Mills NL, et al. Diesel exhaust inhalation increases thrombus formation in man. Eur Heart J. 2008 Dec;29(24):3043-51.
- Miller MR, Shaw CA, Langrish JP. From particles to patients: oxidative stress and cardiovascular effects of air pollution. Future Cardiol. 2012, 8, 577-602.
- Hussain M, Wu D,Saber AT, et al.Intrathecheally instilled titanium dioxide nanoparticles translocate to heart and liver and activate complement cascade in the heart of C57BL/6 mice. Nanotoxicology 2015, 9,1013-1022.
- Meiring JJ, Borm PJ, Bagatelle K, et al. The influence of hydrogen peroxide and histamine on lung permeability and translocation ofiridum nanoparticles in the isolated rat lung. Part. Fibre. Toxicol. 2005, 2, 3.
- Bakian AV, Huber RS, Coon H, et al. Acute air pollution exposure and risk of suicide completion. Am J Epidemiol. 2015;181(5):295-303.
- Power MC, Kioumourtzoglou MA, Hart JE, Okereke OI, Laden F, Weisskopf MG. The relation between past exposure to fine particulate air pollution and prevalent anxiety: observational cohort study. BMJ. 2015 Mar 24;350:h1111.
- Pirela SV, Martin J, Bello D, Demokritou P. Nanoparticle exposures from nano-enabled toner-based printing equipment and human health: state of science and future research needs.Crit Rev Toxicol. 2017 May 19:1-27.
- Jayaram DT, Runa S, Kemp ML, Payne CK. Nanoparticle-induced oxidation of corona proteins initiates an oxidative stress response in cells. Nanoscale. 2017 May 24.