Challenges of Regulation and Risk Assessment of Nanomaterials

7. HUMAN TOXICITY
7.1. Summary record
The human toxicity session included presentations on biokinetics, genotoxicity, acute toxicity and
other toxicity endpoints relevant for the human health risk assessment.
The toxicology session was introduced by presenting the results of a risk assessment appraisal
performed with four kinds of manufactured nanomaterials under the ENRHES (i.e. Engineered
Nanoparticles: Review of Health and Environmental Safety) project. The methodology to derive limit
values following the REACH guidance (i.e. DNELs = derived no-effect levels) was compared to other
methodologies for deriving limit values recently published. It was shown that depending on the
methodology there can be big differences. Further, great variation exists in occupational exposure
values reported in the literature. Consequently, depending on the methodology and exposure values
considered, different conclusions on the presence or absence of a risk are reached. During the
discussion it was highlighted that for the hazard and risk assessment, consideration of genotoxic
effects of nanomaterials and whether these are threshold or non-threshold is crucial. Based on the
available data there are however no generalisation possible across nanomaterials and each
evaluation has to be made on a case by case basis.
During the consequent discussion and a later presentation on biokinetics it was highlighted that the
exposure duration is an important factor for assessing the risk, as it is difficult to draw conclusions
from either the absence of or relatively low toxicity observed under subchronic - chronic exposure
conditions. For example, carbon nanotubes can be inhaled and deposited in the lungs as bundles,
which may not be a stable form of the CNT, and some individual CNT can be released over time.
Therefore adverse effects would only elucidate over chronic exposure, as it may be also expected for
rather inert nanomaterials with no/low short term toxicity but possible adverse effects under chronic
conditions due to accumulation. In addition, the possibility of translocation should always be
considered. The dedicated presentation later during that session highlighted the importance of
considerations of the ENM accumulation in secondary target organs following chronic exposure.
Following pulmonary exposure, nanomaterials (20 nm TiO2, gold, iridium and carbon) will
predominantly be retained in the lung, but approximately between 1 and 10% can slowly be
translocated across the air-blood-barrier. There are significant differences in translocation between
different sizes and materials in relation to distribution to secondary organs, such as liver, spleen,
kidneys, heart and brain, but also skeleton and soft tissues. The distribution pattern differs between
intravenous injection and pulmonary exposure, however one study indicated that the biodistribution
of inhaled and intratracheally instilled nanoparticles (20 nm gold) was similar, suggesting that
intratracheal instillation studies could for many purposes replace the costly inhalation studies. This
may however need further validation. Stable radiolabelling plays an important role in the detection of
low nanomaterial concentrations in different organs, and it allows ENM detection over 5 orders of
magnitude (important for chronic exposure). Better understanding of how size and composition
affects absorption is needed, and based on that it might be possible to build models for estimating
the translocation. Further work is also needed to understand the absorption of soluble nanomaterials
such as nano-silver.
The next speaker presented the results of genotoxicity studies (Micronuclei and Alkaline Comet
assay) on silica ENM, which had to be adapted to avoid interference of nanoparticles with the test
result (e.g. interference with serum). The speaker concluded that the alkaline comet assay and the
micronucleus (MN) assay with adaptations are suitable tests to study in vitro genotoxicity of insoluble
ENM. The MN assay was also proposed as pre-validation study to be used for hazard assessment. The
need of adaptation, however, implies that one has to be careful with the interpretation of published
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