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EC number: 200-001-8
CAS number: 50-00-0
Cell proliferation: Clear
dose-response trends at all three exposure durations with increases seen
at 6, 10, and 15 ppm but not at the two lower exposure concentrations.
nasal lesions (predominantly inflammation, squamous cell metaplasia, and
epithelial hyperplasia) were found in the respiratory/transitional
epithelium in rats exposed to 2 ppm FA or higher.
At higher exposure concentrations >6
ppm and especially the 1-week exposure, there was erosion or ulceration
of respiratory epithelia and/or necrosis of underlying structures. The
incidence of the lesions was related to the inhaled concentration and
inversely related to the exposure duration; with longer exposure, the
more robust squamous epithelium showed less erosion than did the
respiratory epithelium it had replaced.
Gene Expression Profiling: The total
number of genes that was significantly altered across all concentrations
and durations was 2197, but patterns of gene expression varied with
exposure concentration and duration. Although at 13 weeks the numbers of
genes significantly up- and downregulated were higher than at 1-week and
4-week exposure, no grouping of genes appeared to be uniquely associated
with this longer duration, as had been observed at shorter exposures.
Enrichment analysis was performed on
the highest three concentrations at all exposure durations and for the
up- and downregulated gene groupings at 1 and 4 weeks, and indicated a
diverse suite of enriched pathways. The top 10 of these pathways
includes Wnt, TGF-beta, Erbb and Hedgehog signalling, as well as
pathways related to DNA repair and cell cycle. At 10 ppm, 8 of 10 of the
top pathways were cell cycle related with the two others related to DNA
damage and Erbb signaling. At 15 ppm, cell cycle and DNA damage were
represented; however, cell adhesion and immune response pathways were
At the 1-week 15 ppm exposure
concentration, a widespread activation of various immune response
pathways likely associated with an inflammatory response following
cytotoxicity was observed. Benchmark doses for significantly enriched
pathways were lowest at 13 weeks. Seven genes, in previous studies found
to be upregulated genes at lower exposure concentrations, were combined
in a ‘‘Sensitive Response Genes’’-grouping (SRG) and had the lowest BMD
of 1 ppm.
PK analysis: The PK analysis showed
that the lower two inhaled FA concentrations (0.7 and 2 ppm) would be
characterized by only minor changes in cellular GSH and intracellular
FAcetal. Above 4 ppm, FAcetal increases with a steeper dose response and
free GSH is reduced to much more significant degree.
Transcriptional and histological
changes corresponded to the dose ranges in which the PK model predicted
significant reductions in free GSH and increases in FAcetal. Genomic
changes at 0.7–2 ppm likely represent changes in extracellular FAcetal
and GSH. DNA replication stress, enhanced proliferation, squamous
metaplasia, and stem cell niche activation appear to be associated with
FA carcinogenesis. At 2 ppm, sensitive response genes (SRGs)—associated
with cellular stress, thiol transport/reduction, inflammation, and cell
proliferation—were upregulated at all exposure durations. Dose
dependencies in MOA, high background FAcetal, and nonlinear FAcetal/GSH
tissue kinetics indicate that FA concentrations below 1 or 2 ppm would
not increase risk of cancer in the nose or any other tissue or affect FA
homeostasis within epithelial cells.
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