Health Effects of Metals in Ambient Air Particulate Matter - Aerosols: Measurement, Dosimetry, and Health Effects - page 367

elemental carbon) late at night. The biological bases for these various associations and their temporal
lags are not known at this time, but may have something to do with the differential solubility of the
PM 2.5 components at the respiratory epithelia, and their access to cells that release mediators that
reach the cardiovascular system.
One important parameter that was not addressed in the above study, but that could inluence
metals' ability in mediating biological response is the extent of soluble metal components present in
the PM 2.5 mass. In a follow-up subchronic PM 2.5 CAPs inhalation study of ApoE −/− mice at 85 μg/m 3
(Lippmann et al., 2006), there was a dramatic change in cardiac function in the fall months in the
ApoE −/− mice. As previously discussed, the 14 days with northwest winds carried more Ni, Cr, and
Fe, but less of the other elemental tracers than the 89 days with winds from all other directions,
and were associated with signiicant increases in HR and signiicant decreases in HRV (Lippmann
et al., 2006). V was lower than normal on the 14 days with unusually high levels of Ni, Cr, and Fe
in this mouse study. Back-trajectory analyses from Sterling Forest for the 14 days with northwest
winds led through lightly populated areas to Sudbury, Ontario, which is the location of the largest
Ni smelter in N. America. At the end of the 6 months of exposure in this study, Sun et al. (2005)
compared the mice in the CAPs exposed subgroup on a high fat diet (HF) with those exposed
to iltered air (FA). For the CAPs-exposed mice, the plaque area in the aorta was 41.5% versus
26.2% (p = 0.001), while for the subgroup on a normal diet, the CAPs-exposed difference versus
FA was 19.2% versus 13.2% (p = 0.15). Lipid content in the aortic arch in the HF versus NC groups
exposed to CAPs was 30% versus 20% (p = 0.02). Vasoconstrictor challenges in the thoracic aorta
were increased in the CAPs-exposed HF mice versus the FA mice (p = 0.03), and relaxation in
response to acetylcholine was greater (p = 0.04). In addition, HF mice exposed to CAPs had marked
increases in macrophage iniltration, expression of inducible NO-synthase, ROS generation, and
immunostaining for 3-nitrotyrosine (all with p < 0.001. Thus, the 30 h/week subchronic CAPs
exposure of ApoE −/− mice at 85 μg/m 3 altered vasomotor tone, induced vascular inlammation, and
potentiated atherosclerosis.
14.3.4 i nHalation s tudies in a niMals witH PM c oMPonents
This section summarizes some studies that used PM components that have been known to produce
signiicant health-related effects at concentrations that are relevant to current or recent human
exposures, but does not cover studies with complex mixtures or pure materials at much higher
concentrations that are not considered to be relevant to subsequent comparisons of results from the
CAPs studies.
Campen et al. (2001) examined responses to Ni and V in conscious rats by whole-body inhalation
exposure. The authors tried to ensure valid dosimetric comparisons with prior instillation studies,
by using concentrations of V and Ni ranging from 0.3 to 2.4 mg/m 3 . The concentrations used
incorporated estimates of total inhalation dose derived using different ventilatory parameters. HR,
core temperature, and ECG data were measured continuously throughout the exposure. The rats
were exposed to aerosolized Ni, V, or Ni + V for 6 h/day for 4 days, after which serum and BAL
samples were taken. While Ni caused delayed bradycardia, hypothermia, and arhythmogenesis at
concentrations >1.2 mg/m 3 , V failed to induce any signiicant change in HR or core temperature, even
at the highest concentration. When combined, Ni and V produced observable delayed bradycardia
and hypothermia at 0.5 mg/m 3 and potentiated these responses at 1.3 mg/m 3 to a greater degree than
were produced by the highest concentration of Ni (2.1 mg/m 3 ) alone. The results are suggestive of a
possible synergistic relationship between inhaled Ni and V, albeit these studies were performed at
metal concentrations orders of magnitude greater than their typical ambient concentrations.
In a second study using dogs with preexisting cardiovascular disease, Muggenburg et al. (2003)
evaluated the effects of short-term inhalation exposure (oral inhalation for 3 h on each of three
successive days) to aerosols of transition metals. HR and the ECG readings were studied in conscious
beagle dogs (selected for having preexisting cardiovascular disease) that inhaled respirable particles