Biomedical Engineering Reference
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to the particular use. As shown in Table 19.1, this could—in principle—include all
routes, that is, dermal, oral, and inhalation, as well as all different time frames from
acute to long-term exposure. Hazard and risk from exposure via different routes can
be described with either route-specific (i.e., oral, dermal, and inhalation) toxicity stud-
ies or by route-to-route extrapolation from one representative mode of exposure. Such
route-to-route extrapolation can significantly reduce animal experiments, but requires
a good understanding of the toxicokinetic behavior. Moreover, route-to-route extrapo-
lation can usually not be applied for local effects such as inflammatory and functional
changes in the lung as observed following nanosilver inhalation (see the following).
Likewise, extrapolation from short-term studies to long-term exposures may be pos-
sible, and extrapolation factors have been recommended for chemicals. However, a rea-
sonable understanding of the relevant mechanisms of toxicity and kinetic aspects (e.g.,
accumulation) should be considered a prerequisite of such time extrapolation. OECD
WPMN has concluded on this issue:
“Ideally the use of long(er) term or chronic data
is recommended over extrapolation from acute or subchronic to chronic. If these data
are not available and default assessment factors are used, this source of additional
uncertainty to the RA should be noted”
(OECD 2012). In addition, information on haz-
ard may need to cover not only the particular nanoform of nanosilver as manufactured
but also all relevant transformation products to which humans may become exposed
along the materials lifecycle (also refer to the earlier section).
There has been a series of reviews of the publicly available database on mam-
malian toxicity of nanosilver over recent years. In 2009, Wijnhoven et al. identified
various data gaps, namely an insufficient understanding of the toxicokinetic behav-
ior including transformation of nanosilver; the influence of particle properties on
toxicity and the contribution of silver ion release; the potential for developmental
and reproductive toxicity as well as neurotoxicity and carcinogenicity; and finally,
the impact of long-term exposures (Wijnhoven et al. 2009).
Since then, the amount of information available on mammalian toxicity of nanoscale
silver has continuously increased. Nevertheless, the EPA has concluded in December
2011 that the studies available then did not cover all life stages and did not address all
relevant endpoints. In particular, no studies on chronic toxicity, reproductive and devel-
opmental toxicity, and carcinogenicity could be identified. Dose-dependent changes in
cytokine levels (IL-1, IL-4, IL-6, IL-10, IL-12, and TGFβ), an increase in serum IgE
levels, and a decrease in the CD4/CD8 T-lymphocyte ratio in an oral 28-day study in
mice reported by Park et al. (2010) raised questions about potential immunotoxicity of
the tested nanosilver. Although no increase in micronucleated polychromatic erythro-
cytes was detected in an earlier study by Kim et al. (2008), the relevance of this finding
for an overall conclusion on mutagenicity was disputed in the absence of informa-
tion on distribution of the tested nanosilver to the bone marrow (US EPA 2011). The
Agency responded to this situation by applying an uncertainty factor of 10 to account
for the overall quality of the database and choosing the effects on immune parameters
observed in mice as point of departure for assessment of oral, dermal, and inhalation
exposures. In addition, authorization of the product under review occurred under the
condition that the manufacturer makes available—depending on refinement of expo-
sure assessment—further toxicity data, namely a subchronic inhalation and/or oral
study with a bone marrow micronucleus assay and a detailed assessment of neurotoxic
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