Chemistry Reference
In-Depth Information
CHAPTER
7
Interactions in Metal Toxicology
GUNNAR F. NORDBERG, LARS GERHARDSSON, KARIN BROBERG,
MOIZ MUMTAZ, PATRICIA RUIZ, AND BRUCE A. FOWLER
ABSTRACT
interactions among groups of metals and metalloids.
At present, there is much to be learned about interac-
tions among both toxic and essential elements, but this
is clearly a critical area of research.
Human exposures to metals and metalloids such
as arsenic frequently occur as mixtures, and hence it
is important to consider interactions among these ele-
ments in terms of both mechanisms of action and for
risk assessment purposes. Interactions among these
elements may produce additive, synergistic/potentia-
tive, or antagonistic effects that may be manifested as
direct cellular toxicity (necrosis or apoptosis) or carci-
nogenicity. Dose-response relationships may further be
infl uenced by constitutive factors such as age, sex, and
the expression of specifi c proteins. The roles of molecu-
lar factors regulated by specifi c genes (so called gene-
environment interactions) for the expression of metal
toxicity are known only to a limited extent for most
metals. However, for chronic beryllium disease causing
fi brosis of the lung, it has been shown that beryllium
sensitization, a prerequisite for developing the dis-
ease, depends on an antigen-specifi c immune response
occurring predominantly among persons with a spe-
cifi c HLA-DBP1 genotype. Some gene-environment
interactions in terms of genetic polymorphisms have
been demonstrated such as those involving ALAD
and arsenic methyl transferases, but the importance of
these observations for development of human diseases
has not been fully explored. Mechanisms of impor-
tance for interactions and the development of toxicity
are the expression of metal-binding proteins (metal-
lothioneins or lead-binding proteins). In many cases,
direct primary data on interactions among toxic or
essential elements are lacking, and so innovative deriv-
ative methods such as the binary weight of evidence
(BINWOE) method have been used to predict potential
1 INTRODUCTION
Toxic effects of metallic compounds may be modi-
fi ed in a number of ways by various factors, changing
the character of effects or dose-effect and dose-response
relationships. Nutritional and physiological factors
may affect susceptibility. Constitutional factors like
age, sex, and other genetically determined factors,
often called host factors, may also be of importance.
Toxicokinetics of metals can also be modifi ed by simul-
taneous or previous exposure to certain environmental
agents. Direct interaction with the metal in question
at the molecular level explains some interactions,
whereas in other cases, an indirect metabolic change
is induced by the interfering environmental factor that
gives rise to the change in dose-response relationship.
Such indirect interactions are sometimes of consider-
able interest even though the mechanism may not be
known. Important interactions may also occur in the
general environment and exposure media (i.e., air,
water, and food), and they are dealt with in Chapter
13. These interactions and environmental transforma-
tions, to a large extent, determine the type of exposure
for human beings. Such interactions are not discussed
in this chapter.
For several decades, chemical and physical interac-
tions of metals have been studied in experiments both
in vitro
and
in vivo
. There is an abundance of data on
