Toxicology of Industrial Compounds

46 SIZING UP THE PROBLEM OF EXPOSURE EXTRAPOLATION
precision. In the main the data have come from drugs but the same general
considerations would hold for environmental chemicals.
Wherever possible the only compounds included in the analysis have
been those where unbound clearance after systemic administration has been
reported, unless it has been shown that there are little interspecies
differences in protein binding or that absorption is known to be complete
in all the animals. In the past these provisos have not always been met,
leading to incorrect interpretation of the data. In most reports the
allometric scaling has used results from at least four species but in some
cases up to 11 have been included. Practically this would involve an
enormous resource and would be difficult when many compounds are
being investigated. For this analysis it has been assumed that only one
species will initially be used and the aim of this analysis was to find which
single species would provide the best prediction of clearance compared to
that found in man.
Three methods have been used using data, wherever possible, from
mouse, rat, rabbit, dog and monkey (macaques) in a total of 60
compounds, with human unbound clearances ranging from 4 to 150 909 ml
min −1 .
Simple allometric equation
Figure 4.1 shows a typical allometric relationship for the clearance of the
anticancer drug, fotemustine, showing that equation (4.1) can be made
linear for the determination of the variables by logarithmically
transforming the body weight (W) and clearances (CL), as shown in
equation (4.2) where the exponent b can be calculated from the slope of
the linear regression.
(4.2)
From this analysis of all the available papers, where this has been
undertaken with more than four species using data taken from 29
compounds, it was possible to show that the mean exponent (b) is
approximately 0.70±0.15 for unbound clearance, but with a range of 0.92–
0.28. This mean value is to be expected since it is comparable to the
exponent for the allometric equation relating physiological rates and
clearances to weight as for metabolic rate, body surface area, hepatic and
renal blood flow, etc. Therefore it would seem that even without a specific
knowledge of the clearance in a number of different species, it could be
assumed that the exponent of 0.7 is a common factor for all chemicals, if it
has not been previously determined. The coefficient a can subsequently be
determined for each compound from only one species according to
equation (4.1), and a predictive value for man determined.