September 16, 2022 - Nanomaterials and Nanofibers

Toxics Use Reduction Institute Science Advisory Board Meeting Minutes

Members Present: Robin Dodson (Chair), Christine Rioux (Vice Chair), Heather Lynch, Wendy Heiger-Bernays, Rich Gurney, Denise Kmetzo, Lisa Cashins, Christy Foran

Members not present: Helen Poynton

Program staff present: Liz Harriman (TURI), Heather Tenney (TURI), Caredwen Foley (OTA), Sandy Baird (Mass DEP)

Others present: Carol Holahan (Foley Hoag ACC), Christina Bramante (Nano-C), Raza Ali (ACC), Tom Lada (Nano-C), David Jones (Arxada LLC), Katherine Robertson (MCTA), Jerome Lang (Nano-C), Dave Williams (former SAB chair), Ryan Bouldin (Bentley University), John Monica (Offit Kurman), Erin DeSantis (ACC)

Welcome & Introductions

The chair noted that this meeting is being conducted remotely, consistent with An Act Relative to Extending Certain State of Emergency Accommodations signed by Governor Baker on June 16^th 2022. This allows the extension of the remote meetings under the Open Meeting Law until March 31, 2023. Board members introduced themselves, program staff were announced, and attendees were asked to put their name and affiliation in the chat.

Approve June Meeting Minutes

A motion was made to approve the June meeting minutes as amended (remove extra ‘and’ under the fourth bullet and fix ‘installation’ autocorrects), and there was a second. A roll call vote was conducted and five members voted in favor, three abstaining.

Single Walled Carbon Nanotubes (potential vote)

At our March meeting the board made a recommendation to list multi-walled carbon nanotubes based on the evidence of pulmonary toxicity, lung cancer, mesothelioma, and environmental persistence. Additional concerns for genotoxicity and toxic environmental degradation products were noted.

The nano petition also asked us to consider carbon nanofibers and single walled carbon nanotubes. We discussed carbon nanofibers at our April meeting, yet did not come to a conclusion. We began discussion of single walled carbon nanotubes at our May meeting and continued in June. At our May and June meetings we noted very high persistence, overall inflammatory effects, generation of reactive oxygen species and DNA damage.

At our last meeting we made a draft summary statement:

There is evidence that SWCNT cause pulmonary toxicity in animals, including inflammation, fibrosis, and granulomas. There is a lack of understanding, however, whether the high doses used in the animal studies exceed particle overload conditions, which are common with poorly soluble particles administered via inhalation. Particle overload overwhelms particle clearance mechanisms, resulting in tissue irritation, release of inflammatory cells, and generation of reactive oxygen species (ROS). Persistent lung inflammation can cause cell proliferation and tissue remodeling, which when insufficiently repaired can lead to non-neoplastic effects such as fibrosis, DNA damage, and possibly, tumor formation. Particle overload conditions are not a response to the agent but rather to the overload conditions.

New information since the last meeting is primarily the additional comments from Nano-C received on September 5^th, background information on particle overload, and two new repeat dose studies.

While dosing is relevant to particle overload discussions, it is important to remember to focus on hazard.

A member noted that while we aren’t doing dose response, high doses that provoke overload conditions inhibit clearance mechanisms.    Rats respond to overload in ways you wouldn’t expect in humans.  Length and other factors drive fibrotic potential. Is it possible to determine for a given study whether it is overload or not?  

A member asked if we could we get a table that we could look at differences between instillation, bolus and outcomes.  It would be helpful to see results comparatively.  It was noted Shvedova had high doses while a couple other papers had lower doses.  Differences in species were questioned -many of the single-walled studies were in mice. In vitro studies, such as Teeguarden don’t rely on how an animal is dosed. Is there evidence from other systems and qualitatively is there a plausible biology for effects?

A good review that was trying to get at the Adverse Outcome Pathway is Vietti 2016, and there is evidence of AOP without overload, suggesting fibrotic effects without overload. For example, single-walled carbon nanotubes may be directly impacting fibroblasts. 

A member notes that Ema 2016 listed out a number of studies, mostly instillation, and that could also be a helpful place to compare lower exposures to higher. Teeguarden and Vietti indicate evidence for molecular changes that don’t depend on dose, support that molecular events in the lung are occurring which are not dependent on the bolus. 

A member noted that keeping track of the physical-chemical properties (agglomerated, metals, wet/dry, purified or not, functional groups) and looking for trends, is overwhelming. If we need to discount certain studies (high dose, rat, instillation) then the studies left also may address only a narrow situation.  Every study is unique.

Heather shared the guidelines for listing and delisting: “reasonably expected to cause serious or irreversible effects” and also noted that how we see chemicals being used in industry can be very different than what the manufacturer intended or recommends.

A member noted that there is evidence of pulmonary toxicity across many different CNTs and situations, so perhaps the specific characteristics don’t matter. The  suggestion of ‘airborne and unbound’ would be too specific for a listing recommendation; a broader class grouping would be better.  Another member noted that the board had looked at a lot of studies and while much of the information is quite specific, the board’s job is to coalesce with a general conclusion.

Visitor Questions/Comments

Christina Bramante cautioned comparing different substances – specifically carbon black and single-walled carbon nanotubes. The structures make a difference in the effects and there are different purity profiles.

Tom Lada noted that for disposal, incineration is required to be very efficient, and will oxidize carbon nanotubes to CO2, and so would not result in significant release of SWCNTs to the environment.  He also noted the impact seen in the various studies of length, diameter, and process conditions, which makes more specificity for listing seem appropriate. Perhaps a class of single walled carbon nanotubes is too broad.

Continued Board Discussion

A member suggested starting with the summary statement from the last meeting:

There is evidence that SWCNT cause pulmonary toxicity in animals, including inflammation, fibrosis, and granulomas. There is a lack of understanding, however, whether the high doses used in the animal studies exceed particle overload conditions, which are common with poorly soluble particles administered via inhalation. Particle overload overwhelms particle clearance mechanisms, resulting in tissue irritation, release of inflammatory cells, and generation of reactive oxygen species (ROS). Persistent lung inflammation can cause cell proliferation and tissue remodeling, which when insufficiently repaired can lead to non-neoplastic effects such as fibrosis, DNA damage, and possibly, tumor formation. Particle overload conditions are not a response to the agent but rather to the overload conditions.

A member noted that we don’t need all that detail around particle overload - we see a variety of impacts, but still see effects irrespective of the dose. Another member noted evidence of non-particle overload based toxicity in the lung. A member suggested that they would flip the draft statement to note effects first that are associated with the material, and then acknowledge that some effects are from particle overload.  Another member recognized that many of the studies need to be interpreted in light of particle overload, but there is a body of evidence that shows pulmonary effects, including inflammation, fibrosis, and granulomas, and supporting in vitro studies such as Teeguardan.

Fibrosis evidence from both in vitro and in vivo studies supports the statement about pulmonary toxicity. Ema 2016, notes that well dispersed acid functionalized SWCNT have a greater effect– more dispersed (they disperse easily in aqueous solution) would not be overload (Saxena 2007). We should not limit to only inhalation studies-from hazard perspective and we don’t need to dismiss instillation. Additionally, some studies also showed effects down the road.

Oberdorster stresses the need for acute and chronic inhalation studies with a range of doses.  We have those, and molecular studies such as Jiang and Teeguarden, and effects associated with more than just the highest dose. 

A member noted that lack of environmental degradation and evidence of genotoxicity statements we made based on our previous discussion.  Along with in vitro data, this may require less from the in vivo studies.

There is not a firm cutoff for particle overload.  We can look at key events before fibrosis with really low doses for predictive effects and have a statement that there could be a progression of effects as dose increases that eventually get you to particle overload.  While we are considering particle overload, we do not need to come to definitive conclusions about it. We should be clear about rationale.

Next Meeting Aim for Mid –November

Adjourn

Visitor Comments (inserted verbatim from zoom chat)