Respiratory and Cardiovascular Effects of Metals in Ambient Particulate Matter: A Critical Review - Reviews of Environmental Contamination and Toxicology - page 162

“group” in the previous studies were similar to the typical number of rats or mice
used per treatment group in the in vivo studies that follow. In both the human and
animal instillation studies, the method of exposure and the physical form of the PM
metals are not “natural,” raising the possibility that invasive physical manipulation
of the subjects may infl uence the responses being measured. The response to a bolus
of aqueous metal extract deposited in a relatively small anatomical region of the
respiratory tract cannot be discounted as a potential explanation for some of the
effects on BALF parameters observed in both the human and animal studies.
The CAPs inhalation studies conducted by Huang et al. ( 2003 ) and Urch et al.
( 2004 ) represent a more “natural” exposure scenario than the bronchial instillation
studies. Although these exposures cannot be considered “real world”, because the
levels of transition metals are many times higher than ambient levels, the compo-
nents in the PM mixture are in the same proportions. It should be noted that the
activity of other components of ambient PM, other than ozone (Urch et al. 2004 )
that would also be concentrated by the technology, was not accounted for in these
studies. Although the levels of metals in CAPs are many times the ambient levels,
this exposure method seems potentially relevant for conducting future human and
animal studies that maximize the chances of detecting responses potentially associ-
ated with PM metals.

3.3.2 In Vivo Studies

As discussed in the previous section, human exposure studies provide some limited
support for the role of metals in the increased morbidity and mortality associated
with increases in ambient PM reported in epidemiologic studies. Human exposure
studies introduce sources of variability in both exposure and response variables that
are diffi cult to control. In vivo studies with laboratory animals (primarily rats and
mice) allow for greater control of the exposure, greater numbers of (almost) geneti-
cally identical subjects, and optimal evaluation of multiple response parameters in
an intact biological system. In contrast, in vivo animal studies do not capture the
inherent (but problematic) variability in either exposures to PM metals or to indi-
vidual human responses. Also, the doses administered to laboratory animals on a
body weight basis are typically several orders of magnitude higher than encountered
by people breathing ambient air containing metals in the low ng/m 3 concentration
range. Extrapolating from animals to humans and from high dose to low dose is not
a straightforward exercise.
The majority of the laboratory animal studies discussed in this section were con-
ducted by multi-institutional teams of researchers in collaboration with the US EPA
National Health and Environmental Effects Research Laboratory (NHEERL), and
followed similar experimental designs. Another distinct group of studies were con-
ducted by investigators in Europe and primarily focused on the activity of PM from
regional airsheds with differing source contributions. In most of the in vivo studies
that we reviewed, the response parameters that were measured are cellular and
chemical indicators of respiratory tract infl ammation and cell damage/death.