Prediction of Toxicity, Sensory Responses and Biological Responses with the Abraham Model Page: 284

                                
A more recent analysis has been carried out (Luan et al., 2006), using the previous data and
division into physical and chemical mechanisms. For 47 VOCs acting by a physical
mechanism, Eqn 43 was obtained.
Log (1/RD50) = -5.550 + 0.043 " Re + 6.329 " RPCG + 0.377 " ICave + 0.049 "   (43)
CHdonor - 3.826 "RNSB + 0.047 ZX
(N = 47, SD = 0.362, R2 = 0.844, F = 36.1)
The statistics of Eqn 43 are not as good as those of Eqn 42, and since some of the descriptors
in Eqn 43 are chemically almost impossible to interpret (ICave is the average information
content and ZX is the ZX shadow) it has no advantage over Eqn 42. What is of more interest
is that it was possible to derive an equation for VOCs acting by a chemical mechanism (Luan
et al., 2006),
Log (1/RD50) = 8.438 + 0.214 " PPSA3 + 0.017 " Hf - 22.510 " Vcmax + 0.229 "  (44)
BIC + 44.508  (HDCA + 1/TMSA) + 0.049 "BOminc
(N = 67, SD = 0.626, R2 = 0.737, F = 28.0)
Although, again, Eqn 44 is chemically difficult to interpret, it does show that it is possible to
estimate RD50 values for VOCs that are reactive and act through a chemical mechanism.
About 20 million patients receive a general anesthetic each year in the USA. In spite of
considerable effort the specific site of action of anesthetics is still not well known. However,
even if the actual site of action is not known, it is possible that a general mechanism on the
lines shown in Figure 4 obtains. In the first stage the anesthetic is transported from the gas
phase to a site of action, and in the second stage interaction takes place with a target
receptor, a variety of which have been suggested ((Franks, 2006; Zhang et al., 2007; Steele et
al., 2007). Then if stage 1 is a major component, we might expect that a QSAR could be
constructed for inhalation anesthesia. It is noteworthy that a QSAR on the lines of Eqn. 2
was constructed for aqueous anesthesia as long ago as 1991 (Abraham et al., 1991). Since
then, rather little has been achieved in terms of inhalation anesthesia. The usual end point in
inhalation anesthesia is the minimum alveolar concentration, MAC, of an inhaled anesthetic
agent that prevents movement in 50 % of subjects in response to noxious stimulation. In rats,
this is electrical or mechanical stimulation of the tail. MAC values are expressed in
atmospheres, and correlations are carried out using log (1/MAC) so that the smaller is MAC
the more potent is the anesthetic. It was shown (Sewell and Halsey, 1997) that shape similarity
indices gave better fits for log (1/MAC) than did gas to olive oil partition coefficients, but the
analysis was restricted to a model for 10 fluoroethanes for which R2 = 0.939 and a different
model for 8 halogenated ethers for which R2 = 0.984 was found. A completely different model
of inhalation anesthesia.has been put forward (Sewell and Sear, 2004, 2006) in which no
consideration is taken as to how a gaseous solute is transported to a receptor, but solute-
receptor interactions are calculated. However, two different receptor models were needed, one
for a particular set of nonhalogenated compounds and one for a particular set of halogenated
compounds, so the generality of the model seems quite restricted.
A QSAR for inhalation anesthesia was eventually obtained using the LFER, Eqn. 3, as
follows (Abraham et al., 2008)
Log (1/MAC) = - 0.752 - 0.034  E + 1.559  S + 3.594 "A + 1.411  B + 0.687  L  (45)
(N = 148, SD = 0.192, R2 = 0.985, F = 1856.1)

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Toxicity and Drug Testing