Published: Aug 13, 2014

By Nancy Walsh, Senior Staff Writer, MedPage Today

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Action Points

• There is some evidence that particulate air pollution may influence risk for and expression of autoimmune disease.
• A particular role for nanoparticles in human disease has not been established.

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Recently, I wrote an article about some interesting research being done by Jean Pfau, PhD, of Idaho State University suggesting that workers who had been exposed to asbestos at the now-shuttered Zonolite mine in Montana were developing an as-yet undescribed autoimmune condition characterized by severe pain and restricted breathing.

Shortly thereafter, I received a phone call from Graham Cliff, PhD, of the University of Manchester in England, who has been a materials scientist for 40 years specializing in the health hazards of minute particles, including asbestos. He told me that the dangers of particle exposure extend far beyond asbestos, and suggested that I look into the effects of both air pollution and the emerging scientific discipline of nanoparticles, in which ultrafine particles are engineered for specific mechanical and biochemical properties.

“Little is known about what happens when people or the environment are exposed to nanoparticles. Authorities such as our prime minister say they want to do the right thing and protect the environment and public health, but that it’s too expensive,” Cliff said.

“We should be warning people today about this. There’s no regulation for these small particle exposures,” he told MedPage Today.

But others disagree, signals and evidence have been mixed, and many questions remain.

Pollution and RA

It’s been well established for a decade that cigarette smoking is a strong environmental risk factor for rheumatoid arthritis (RA) in genetically susceptible individuals, presumably because of an epigenetic process in the lung known as citrullination.

In this post-translational process, the amino acid arginine is replaced by citrulline, which alters genetic expression and protein structure, and can result in autoantibody formation and systemic loss of immune tolerance.

A group of researchers led by Elizabeth W. Karlson, MD, of Harvard Medical School had observed that the incidence of RA seemed to be higher in the Northeast and Midwest, where congestion and air pollution are often worse than in other areas of the country. They wondered if similar events in the lung following inhalation of high levels of particulate matter in traffic exhaust could similarly activate the immune system, resulting in RA.

Accordingly, they analyzed data from the more than 90,000 women in the Nurses’ Health Study, looking at disease incidence as related to distance of residence from major roadways.

On a multivariate analysis adjusting for factors such as cigarette smoking, age, and education, they identified an increased risk for RA among women living within 50 meters of a primary road (HR 1.63, 95% CI 1.06-2.51).

“Human exposure to high levels of ambient particles stimulates the production of inflammatory cytokines in the lung, which may stimulate the bone marrow to release neutrophils and monocytes into the circulation,” they wrote in Environmental Health Perspectives.

However, in a subsequent study also using data from the Nurses’ Health Study, the same authors observed different results.

They obtained estimated levels of two specific pollutants, nitrogen dioxide and sulfur dioxide, as well as particulate matter smaller than 10 microns in diameter (PM10), from the Environmental Protection Agency’s prediction models for the addresses of 111,425 participants.

During more than 3 million person-years of follow-up, there were 858 incident cases of RA, but no association was seen with levels of the individual pollutants, they reported in Arthritis Care and Research.

As to why these findings didn’t correspond to the roadway proximity study, they wrote, “It is possible that the distance to roadway is a proxy for some other exposures (e.g., noise, neighborhood), which may have confounded the association with an increased risk of RA in our previous analyses, or, alternatively, that the measurements of air pollution exposures in the current study were too imprecise or not strongly associated with the etiologically relevant agent.”

JIA and Ambient Air

Another group of researchers led by Andrew Zeft, MD, from the University of Utah, hypothesized that fine particulate pollution might trigger juvenile idiopathic arthritis (JIA).

“As in adult-onset RA, environmental agents are thought to interact with genetic factors that influence susceptibility prior to JIA onset,” they wrote in Pediatric Rheumatology.

To see if concentrations of particulate matter with diameter of 2.5 microns (PM2.5) or less and “stagnant air” were associated with any of the subtypes of JIA, they identified 338 children with JIA enrolled in the Intermountain States Database of Childhood Rheumatic Diseases.

They also collected data on air quality monitoring from the Utah Department of Environmental Quality between 1993 and 2006 throughout the Salt Lake City region.

They found a significant association with high levels of pollution in the 2-week period before JIA onset in preschool-age children (RR 1.60, 95% CI 1-2.54), with the risk being particularly notable for the systemic-onset subtype.

They also observed a significant risk following “prolonged stagnant air days” among preschool children (RR 1.21, 95% CI 1.06-1.38, P=0.004).

The researchers noted that a mouse study had implicated IL-6 production and coagulopathy in alveolar macrophages following fine particulate matter exposure.

“The role of IL-6 in the particulate-induced inflammatory and procoagulant response allows us to speculate whether the inflammatory stimulus in systemic JIA onset, an IL-6 mediated disorder with an underlying coagulation abnormality, is driven in our study by the IL-6 mediated effects of particulate exposures,” they wrote.

Disease Activity in Lupus

Investigators from McGill University in Montreal led by Audrey Smargiassi, PhD, considered the possibility that PM2.5 pollutants could influence lupus disease activity in a cohort of 237 patients enrolled in a registry at their clinic.

Hourly PM2.5 concentrations were recorded by Environment Canada’s National Air Pollution Surveillance network and were averaged for the 2 days prior to individual patients’ clinic assessments.

They evaluated effects on disease activity as determined by levels of two lupus-specific markers, anti-double stranded (ds)DNA and renal tubule cellular casts.

The crude and adjusted odds ratios for a 10-mcg/m3 increase in PM2.5 were 1.26 (95% CI 0.96-1.65) and 1.34 (95% CI 1.02-1.77) for anti-dsDNA antibodies, while for renal cellular casts the ORs were 1.43 (95% CI 1.05-1.95) and 1.28 (95% CI 0.92-1.80).

“Our data suggest that short-term variations in air pollution may influence disease activity in established autoimmune rheumatic disease in humans. Our results add weight to concerns that pollution may be an important trigger of inflammation and autoimmunity,”Smargiassi and colleagues wrote in Environmental Health Perspectives.

Diesel Particles and Scleroderma

Silvana Fiorito, PhD, of Universita Sapienza in Rome, and colleagues hypothesized that very fine particles from diesel engines could trigger the development of the fibrosis characteristic of scleroderma, also known as systemic sclerosis (SSc).

“Particles of nanosized dimension, as small aggregates of carbonaceous particles less than 100 nm, constitute the most part of diesel exhaust particles and represent the greatest concern to human health because they remain in the atmosphere for long periods, invade the indoor air environment, and can be breathed most deeply into the lungs where they are likely to be more toxic than coarse particles,” Fiorito’s group wrote online in the Journal of Immunology Research.

To evaluate the effects of diesel nanoparticles, they performed in vitro tests of fibroblasts and keratinocytes derived from patients with scleroderma and healthy controls exposed to soot from diesel engine exhaust, using PCR to assess changes in gene expression.

They found that the scleroderma cells showed greater activation of fibroblasts and keratinocytes, with significant induction of proinflammatory cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor, as well as increased RNA expression of metalloproteases.

The increase in IL-1 and IL-6 gene expression suggested that “this environmental stimulus could represent a key factor capable of initiating a proinflammatory/profibrogenic cascade in SSc subjects.”

In addition, the higher levels of metalloproteases “are associated with an increasing number of injuries and disorders, such as cancer, inflammation, and autoimmune diseases.”

They also noted that in a previous study, they found that the tiny dimensions of nanoparticles “enable them to be easily and spontaneously internalized by skin keratinocytes … and thus to induce a severe inflammatory response.”

Nanoparticles: A 21st Century Asbestos?

Today, nanoparticles are found in multiple products, ranging from sunscreens and cosmetics to bicycles and automobiles.

Andrew D. Maynard, PhD, director of the University of Michigan Risk Science Center in Ann Arbor, has researched and written extensively on nanoparticles, and has served on national and international panels on nanotechnology.

The term nanoparticle is too nonspecific in terms of health, Maynard explained. “They come in all shapes, sizes, and chemical compositions, and interact with our bodies in very different ways. You can’t lump them all together any more than you can say that a molecule of water is as dangerous as a molecule of cyanide,” he said.

“We have learned that exposure and transmission of particles through the body tend to depend fairly critically on size of the particle, shape, and surface chemistry,” he said.

In addition, when a particle enters the body it acquires a coating of proteins that also helps determine what that particle does in the body, he explained.

“So we know a lot more than we used to about how materials behave in the body but we know very little about how that translates into health impact.”

He took the long view in a recent essay in Toxicological Sciences.

“Humans have developed as a species in the presence of airborne carbonaceous nanoparticles from combustion, and our bodies have evolved to handle exposure to such materials. Since before the industrial revolution, people have been exposed to airborne metal and metal oxide nanoscale particles from hot processes, and while these materials are rarely innocuous, we have an understanding of how they impact on human health.”

But even nanotechnology is relatively new, “one of the things we’ve found over the past 10 years is that we have already evolved being exposed to nanoparticles, and because of that our bodies have learned how to adapt to them, manage them, and work with them. Our bodies are very adept at this,” he told MedPage Today.

Another researcher, Guenter Oberdorster, PhD, of the University of Rochester, asked whether one type of particle, carbon nanotubes, might pose a particular hazard.

“Concerns had been raised earlier that nanoparticles of fibrous shape and dimensions and of high biopersistence, resembling asbestos, may induce adverse effects similar to those known to be caused by asbestos exposure, i.e., lung fibrosis, lung carcinoma, and mesothelioma,” Oberdorster wrote in the Journal of Internal Medicine.

“Although many or even most engineered nanomaterials with a potential for human exposure are not likely to induce adverse effects, it may well turn out that some could cause an asbestos-type disaster if uncontrolled,” he cautioned.

Maynard agreed that many questions remain, including the possibility of disturbances of immune function.

“These are subtle perturbations to the body, which begin to express themselves over time, and it’s not that easy to find the link between causative agent and actual response,” he said.

The approach being taken by the scientific community currently is to ask whether there are plausible causes for specific small particles to be harmful based on what is known about the immune system.

“We can do that to a certain extent with chemicals because we can see how they interlock with different systems with the body and how they can act as triggers. With particles, it’s not so clear at all. The research in this area is still somewhat speculative, and it may be that we end up discovering that some particles can exacerbate or trigger autoimmune responses, but we’re a long way from being definitive on that front,” Maynard said.

For now, consumers who have questions about the safety of products containing nanoparticles such as sunscreens have to “trust in credible sources of information, whether these are government agencies or researchers,” he advised.

“But for most materials that people are being exposed to in consumer products, there is no clear evidence that they present a substantial risk. That may change, new evidence may come to light, but there are no big warning signs at the moment,” he stated.

Rheuminations is a blog by Nancy Walsh for readers with an interest in rheumatology. A follow-up to this piece will address the concern that uranium exposure may be implicated in lupus.