4 research outputs found
Genotoxicity testing of nanomaterials
Nanomaterials have outstanding and unprecedented advantageous material properties but may also cause adverse effects in humans upon exposure. Testing nanomaterials for genotoxic properties is challenging because traditional testing methods were designed for small, soluble molecules and may not be easily applicable without modifications. This review critically examines available genotoxicity tests for use with nanomaterials, including DNA damage tests such as the comet assay, gene mutation tests such as the mouse lymphoma and hprt assay, and chromosome mutation tests such as the micronucleus test and the chromosome aberration test. It presents arguments for the relative usefulness of various tests, such as preferring the micronucleus test over the chromosome aberration test for scoring chromosome mutations and preferring mammalian cell gene mutation tests because the Ames test has limited utility. Finally, it points out the open questions and further needs in adapting genotoxicity tests for nanomaterials, such as validation, reference nanomaterials, and the selection of top test concentrations, as well as the relevance and applicability of test systems and the need to define testing strategies.
This article is categorized under:
Toxicology and Regulatory Issues in Nanomedicine > Toxicology of Nanomaterials
Toxicology and Regulatory Issues in Nanomedicine > Regulatory and Policy Issues in Nanomedicin
Plasmodium chabaudi chabaudi: Differential susceptibility of gene-targeted mice deficient in IL-10 to an erythrocytic-stage infection
Female and male mice deficient in IL-10 production by targeted disruption of the IL-10 gene were infected with Plasmodium chabaudi chabaudi (AS) blood-stage parasites. Both male and female mutant mice exhibited more severe signs of disease than did +/+ or heterozygous control mice. Female defective mice also displayed an increased mortality; 56% of mice died within 20 days of infection. Mortality did not appear to be due to a fulminating parasitemia as death occurred at different levels of parasitemia in the individual mice. The acute infection was accompanied by an enhanced Th1 IFN-gamma response. This response was retained in the chronic phase of infection of both male and female mutant mice, whereas in controls the responding CD4+ T cells were predominantly Th2 cells secreting IL-4. The data suggest that IL-10 regulates the inflammatory response to the parasite and that in its absence the combined effects of malaria toxins and the sustained or enhanced IFN-gamma response lead to increased pathology. In the case of female mice absence of IL-10 is sufficient to induce a lethal endotoxin-like reaction
Assessment of Pre- and Pro-haptens Using Nonanimal Test Methods for Skin Sensitization
Because of ethical
and regulatory reasons, several nonanimal test
methods to assess the skin sensitization potential of chemicals have
been developed and validated. In contrast to <i>in vivo</i> methods, they lack or provide limited metabolic capacity. For this
reason, identification of pro-haptens but also pre-haptens, which
require molecular transformations to gain peptide reactivity, is a
challenge for these methods. In this study, 27 pre- and pro-haptens
were tested using nonanimal test methods. Of these, 18 provided true
positive results in the direct peptide reactivity assay (DPRA; sensitivity
of 67%), although lacking structural alerts for direct peptide reactivity.
The reaction mechanisms leading to peptide depletion in the DPRA were
therefore elucidated using mass spectrometry. Hapten–peptide
adducts were identified for 13 of the 18 chemicals indicating that
these pre-haptens were activated and that peptide binding occurred.
Positive results for five of the 18 chemicals can be explained by
dipeptide formations or the oxidation of the sulfhydryl group of the
peptide. Nine of the 27 chemicals were tested negative in the DPRA.
Of these, four yielded true positive results in the keratinocyte and
dendritic cell based assays. Likewise, 16 of the 18 chemicals tested
positive in the DPRA were also positive in either one or both of the
cell-based assays. A combination of DPRA, KeratinoSens, and h-CLAT
used in a 2 out of 3 weight of evidence (WoE) approach identified
22 of the 27 pre- and pro-haptens correctly (sensitivity of 81%),
exhibiting a similar sensitivity as for directly acting haptens. This
analysis shows that the combination of <i>in chemico</i> and <i>in vitro</i> test methods is suitable to identify
pre-haptens and the majority of pro-haptens