Respiratory and Cardiovascular Effects of Metals in Ambient Particulate Matter: A Critical Review - Reviews of Environmental Contamination and Toxicology - page 189

The majority of the animal studies that we reviewed used instillation of PM
extracts or metal solutions directly into the trachea as the method of dosing. The
delivery of a bolus of particulate to a small area of respiratory tract cells can pro-
voke a response that is not analogous to an inhaled dose that is naturally distributed
across the surface area of the human respiratory tract. Although intratracheal instil-
lation of PM extracts or metal solutions increases the confi dence that the response(s)
of the respiratory tract cells being measured are caused by the substance adminis-
tered, this route of administration is not analogous to breathing PM in ambient air.
Such intratracheal instillation bypasses interactions with the anatomical landscape
from the nose to the lungs. Furthermore, particulates in ambient air do not enter
airways as an aqueous solution deposited directly on airway epithelial cells. Thus,
it is not surprising that instillation of very high doses of particulate or metal solu-
tions cause acute infl ammatory response and death in some of the studies. The
majority of researchers were diligent in using controls. However, when boluses of
concentrated “particle masses” were surgically emplaced, they may have contributed
to infl ammatory responses.
In studies we reviewed, animals were exposed to various doses of Cu, Fe, Mn,
Ni, V and Zn. To estimate a daily dose to humans, we assumed that a 70 kg person
would inhale 10 cubic meters of air per day containing the average concentration of
each metal represented by the STN data (Table 1 ). Our estimated human doses
were: Cu ~0.00077 ʼ g/kg-day; Mn ~0.00043 ʼ g/kg-day; Fe ~0.0134 ʼ g/kg-day; Ni

~0.00019 g/kg-day.

The doses used in the majority of in vivo studies are much higher than what
people are exposed to in ambient air. By putting all dosages on a common footing
(e.g., metal mass per body weight), it is possible to see the extent of the dosage
variation across studies and across the target metals. For example, in human expo-
sure studies using ambient or concentrated (CAPs) exposures (Table 5 ), the median
range of dosages is reasonable, from 1 to 10 times the expected human 24-h dose at
the STN annual mean values. The ambient concentrations of PM metals reported in
industrial regions of Europe were 20-300 times higher than the expected doses in
the U.S. based on STN annual mean values.
The ratios of administered doses to expected ambient doses were much higher in
the toxicology studies that were performed. The median dosage for the studies in
Table 6 , for example, exceeded 1,000 times the expected human 24-h dosage for the
three metals Cu, Ni, and Zn, and 35 times the expected human dose for Fe. Maximum
exposure ratios exceeded one million for Ni and V, but were less than 1,000 for As
and Mn. Minimum exposure ratios were not lower than 100 for any metal. Therefore
some studies exceeded others in dosage levels by as much as 30,000-90,000 times
(Fe, Ni, and V). Moreover, most metals identifi ed as being more toxic were often
chosen a priori as targets of these investigations (e.g., in the many ROFA studies).
In some studies, the concentrations of Ni and V were often two orders of magnitude
higher, on an equal body weight basis, than the other metals tested.
The ROFA studies (Table 8 ) included fi ve target metals, and a wide range of
doses. For example, the median dose levels of Ni and V used in the studies were
170,000 and 770,000 times expected human 24-h doses. The doses of Fe and Mn

ʼ g/kg-day; V ~0.00016 ʼ g/kg-day; and Zn ~0.002 ʼ