Yes, Virginia, inhaled carbon nanotubes do cause lung granulomas

Richard Denison, Ph.D., is a Senior Scientist.

My last post identified two Section 8(e) "substantial risk" notices pertaining to carbon nanotubes, one submitted by BASF, the other by Arkema.  I have in my files one additional Section 8(e) notice for a single-walled carbon nanotube (SWCNT), submitted by DuPont.  With three Section 8(e) notices submitted for different rat pulmonary toxicity studies on carbon nanotubes, it's interesting to compare their results.

The DuPont Section 8(e) notice was submitted to EPA on April 10, 2003 (#8EHQ-0403-15319), but appears not to be available anywhere online.  It reports the results of an intratracheal instillation study in rats, which was among the first to identify the formation of lung granulomas.  The full study was published in Toxicological Sciences in 2004.

Here are a few details of each of the three studies reported in the Section 8(e) notices:

Submitter Material Mode of administration Exposure
Dupont, Apr-03 SWCNT intratracheal instillation one-time exposure,
3-month observation
Arkema, Mar-08 MWCNT inhalation 6 hrs/d for 5 days,
28-day observation
BASF, Aug-08 CNT (unsp.) inhalation 6 hrs/d, 5 d/wk for 90 days

DuPont, both in its Section 8(e) notice and in the published paper, questioned the physiological significance of its finding of granulomas, suggesting it was likely an artifact of the method of administration.  Indeed, the instillation procedure introduced clumps or ropes, rather than individual CNTs, and some heavily dosed animals died of apparent suffocation.  DuPont based its conclusion on a variety of factors, including the apparent lack of dose-response and the absence of other signs of lung toxicity.  It called for inhalation toxicity studies to be conducted to resolve whether the effects it observed were real.

What do inhaled carbon nanotubes do to the lungs?

Via the more recent Section 8(e) notices, we now appear to have confirmation of the ability of CNTs to produce lung granulomas when inhaled.  While there are differences in the nature of the CNT material administered and other study details, both Arkema and BASF report the dose-dependent formation of granulomas.

They also report numerous other signs of lung toxicity, including increased lung weights.  Arkema established 0.1 milligrams per cubic meter (mg/m3) as its short-term no-effect level, while BASF's longer-term study found granulomas at that same dose – the lowest tested – and hence could not establish a no-effect level.

This level of toxicity exhibited in a 90-day repeated dose inhalation study is very high.  To judge toxicity, EPA uses internationally accepted toxicity criteria set forth under the Globally Harmonized System (GHS) of Classification and Labeling.  The GHS "high-concern" classification criterion for a 90-day inhalation toxicity study involving exposure to a dust is a lowest-observed adverse effect level (LOAEL) of less than 0.02 milligrams per liter (mg/L) per day (see Appendix 2, Table 5 of this EPA document).

In the BASF study, the LOAEL was the lowest dose tested, 0.1 mg/m3 = 0.0001 mg/L, which is 200 times lower than the GHS' "high-concern" cutoff value!!

For further context, consider the LOAEL values found in rat subchronic and chronic inhalation studies of another particulate material, respirable crystalline silica.  LOAELs ranged from 1.0 mg/m3 in a 24-month inhalation study to 2.0 mg/m3 in 6-month studies (see Table 18 of this document).  That means the CNTs studied by BASF are at least an order of magnitude more toxic than silica.

Also note that inhaled silica is much more toxic to humans than to rats:  the human LOAEL for inhaled silica for chronic lung disease is far lower than the rat LOAEL, on the order of 0.02-0.05 mg/m3 (see Table 16 of this document).  So if humans are also more susceptible to the effects of CNTs than are rats, the human toxicity level could be far lower than what BASF has observed in rats.

Remember that other recent studies suggest certain MWCNTs can behave biologically rather like asbestos.  Together with these inhalation studies, it's no wonder EPA is requiring inhalation toxicity studies and workplace inhalation exposure controls for CNT producers, as I discussed in a previous post.

But these findings beg the question:  Will that be enough?

[UPDATE:  Thanks to Andrew Maynard's blog post today, I have learned of a new published study by Shvedova et al. that found that administration of SWCNTs by inhalation was actually more effective than administration by pharyngeal aspiration in causing inflammatory responses and other signs of lung toxicity in the lungs of mice.]

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