Health Effects of Metals in Ambient Air Particulate Matter - Aerosols: Measurement, Dosimetry, and Health Effects - page 374

14.5 FURTHER PERSPECTIVE ON BIOLOGICAL PLAUSIBILITY
For most scientists today, biological plausibility for adverse effects caused by ambient air metals
needs to be based on a clear understanding of the underlying biological mechanisms that can
account for the empirical observations arising from laboratory-based exposures or epidemiological
studies of populations in the real world. Until recently, mechanistic understanding, based on in vitro
studies, has been quite sparse, and the evidence for causal relationships between exposures to
ambient air metals and adverse health effects has been more indirect. Of necessity, in the absence of
much knowledge on underlying mechanisms, we have had to rely on the consistency of signiicant
associations between indices of PM mass exposures and speciic responses, their stability over
time and space, and the coherence of each speciic response with other responses that one would
expect to see if the irst was really reliable. In part, this situation was necessitated by the fact that
we have had to rely on exposure indices based on particle mass or number concentrations, and have
seldom had access to the concentrations of the causal components within the PM, and their temporal
concentration variation.
We have only recently begun to have opportunities to frame the questions about underlying
biological mechanisms in conjunction with observational studies of exposure-response relationships.
A broad range of health effects have recently been associated with subchronic CAPs inhalation
studies in rodent models, and it is reasonable to assume, based on this review, that many of these
effects were due to the metals within the CAPs. The following are some examples:
1. Sun et al. (2005) demonstrated that the in vivo CAPs exposure increase of plaque in the
aorta was associated with lipid content, responses to vasoconstrictor challenge, relaxation
in response to acetylcholone, increases in macrophage iniltration, expression of inducible
NO-synthase, ROS generation, and immunostaining for 3-nitrotyrosine.
2. Sun et al. (2008a) demonstrated that the CAPs exposure also increased tissue factor expres-
sion in the aorta.
3. Sama et al. (2007) demonstrated that CAPs that altered brain cell distributions in vivo
caused changes in immortalized microglial cells in vitro , intracellular ATP, depolariza-
tion of mitochondrial membranes, glutathione, nonprotein sulfhydryl, TNF a, IL-6, and
gene regulation. The responses were dose related, with the primary determinant being the
capacity of CAPs to activate NF k B in human bronchial epithelial cells.
4. Sun et al. (2008b) demonstrated that, after CAPs exposure, infusion of angiotensis II
increased mean arterial pressure, potentiated aortic vasoconstriction to phenylephrine,
exaggerated relaxation a Rho-kinase inhibitor, and increased superoxide levels in the
aorta.
5. Sun et al. (2009) demonstrated that the CAPs exposure in an obese mouse model had
insulin-signaling abnormalities that were associated with abnormalities in vascular relaxation
to insulin and acetylcholine, increased adipose tissue macrophages (F4/80+ cells) in visceral
fat, and expression of higher levels of TNF-a/IL-6 and lower levels of IL-10. In coordinate in
vitro tests, PM induced cell accumulation in visceral fat and potentiated cell adhesion in the
microcirculation, supporting a link between CAPs exposure and Type II diabetes mellitus and
metabolic syndrome.
6. In association with their CAPs inhalation study of the inluence of CAPs exposure on
nonalcoholic fatty liver disease (NAFLD), Tan et al. (2009) performed in vitro exposures
using a reference PM sample (NIST SRM1649a). For the mice exposed by injection,
particles were detected only in Kupffer cells from livers not seen in sham injected mice.
Cell culture studies were done using macrophage (RAW) and stellate (LX2) cell lines.
Direct exposure to PM 2.5 activated IL-6 production by Kupffer cells in a TLR4-dependent
manner. Thus, exposure to ambient air PM may be a signiicant risk factor for NAFLD
progression.