The goal of this first
workshop is to develop a research approach for
modeling complex chemico-biological interactions
found at the “soft” end of the reactivity spectrum
where the primary molecular targets of the toxic
agents are selected amino acids, especially cysteine,
in cellular proteins. Specifically the panel of
experts will consider new ways of:
1) identifying the
nature of electrophile reactions;
2) quantitatively
measuring reactivity;
3) modeling
reactivity, and
4) and formulating
relationships between reactivity and toxicity
The acceptance of using
novel approaches to provide estimates of missing
data for chemicals in risk assessment and to aid in
decision making processes is occurring within a
setting of unprecedented international harmonization
of the principles structure-activity modeling,
spurred by the urgent need to develop strategies to
replace animal testing, especially in view of
legislative initiatives such as REACH (registration,
evaluation, authorization of chemicals). QSARs, in
vitro and physicochemical assays and/or non-animal
toxicology assays or combinations of these need to
be developed to serve as surrogates for animal
testing.
Irreversible
molecular reactions between foreign chemicals and
cellular components initiate cellular/organism
toxicity pathways, which can cause a wide array of
adverse outcomes including acute failure of nerve
function, skin irritation/sensitization, immune
system dysfunction, developmental abnormalities,
idiosyncratic organ failure and death, mutagenicity
and carcinogenicity. The formation of a covalent
bond is the key and initiating step along the
pathway of such reactivity toxicity. These
initiating events must be better understood and
modeled in order to predict the potential of
chemicals to cause specific reactive effects.
Reactive toxicity has its foundation in the
classical theories of chemical reactivity. Although
there are numerous conventions for categorizing the
concept of chemical reactivity, the initial theory
for this workshop represents chemical reactions as
interactions of Lewis acids and bases. From this
theory, a Lewis acid is an electron deficient
chemical known as an electrophile which can accept
electrons in the reaction between chemicals. A Lewis
base is an electron rich chemical known as a
nucleophile, which can donate electrons in a
chemical reaction. There are a variety of parameters
in computational chemistry, which relate to the
energetics of the transfer of electrons in
electrophile-nucleophile interactions and the
formation of new bonds. However, chemical reactivity
is often influenced strongly by steric factors as
well, and the quantification of steric parameters is
poorly developed.
This
second dimension to chemical reactivity between
electrophiles and nucleophiles is often described as
a qualitative spectrum of the specific atomic
centers involved in the chemical reaction ranging
from soft electrophilic/nucleophilic centers to hard
electrophilic/nucleophilic centers. A hard
electrophile is one where the electron deficiency
has a localized electrostatic positive charge
whereas a soft electrophile is one will lower charge
spread over a larger atom or molecular region. In
general, the “like-reacts-with-like” rule applies to
these reactions so that soft electrophiles react
preferentially with soft nucleophiles and hard
electrophiles react preferentially with hard
nucleophiles. In biological systems, examples of
soft nucleophiles are the sulfur moieties of
cysteine residues in proteins.
