Toxicology of Industrial Compounds

most processes in the mammalian body have been shown to be
proportional to the body weight of the animal (Adolph, 1949; Calabrese,
1983; Peters, 1983; Chappell and Mordenti, 1991) and can be related by
allometry, a word from the Greek meaning the measurement (metry) of
changing size (allo). It has been shown that blood flow, organ size,
metabolic and respiratory rate, and many other physiological and
anatomical variables are related by the general allometric equation
(Boxenbaum, 1982b):
(4.1)
where Y is the function to be measured, W the body weight of the animal,
a the coefficient and b the exponent. For mammals, whilst a is different for
each function, b is approximately 0.6–0.8 for rates, flows and clearances, 1.
0 for volumes and organ sizes, and 0.25 for cycles and times. Thus
metabolic rate can be calculated from 7.0·W 0.75 , liver blood flow from
37·W 0.85 , blood weight from 0.055·W 0.99 , and respiratory rate from 0.
019·W 0.26 . Since the blood flows and the weights of the liver and kidney,
the two major organs of elimination, can be similarly allometrically scaled,
it follows that the same formula could in principle be used for
extrapolation of the clearance of chemicals between species.
In the past there has been much discussion on the possibility of
predicting human kinetics and distribution from animal data, using
allometry. For industrial chemicals relatively complex physiological models
have been constructed using this knowledge of relative blood flows and
organ size to predict what levels of exposure could be expected in man
(Andersen et al., 1984), but little work has been published on comparative
interspecies clearances which will dictate the circulating levels. For drugs,
on the other hand, a number of reports have been published on the
rationale for the use of allometric scaling of kinetics (Dedrick, 1973;
Boxenbaum, 1982b, 1984, 1986; Mordenti, 1985, 1986; Sawada et al.,
1985; Chappell and Mordenti, 1991) but many have been concerned with
its theoretical aspects rather than with its practical use for prediction.
When scaling has been used, the predictions have not always been
accurate, and the method has therefore not had wide usage. This is
unfortunate since the ability to predict what will be the blood levels in man,
without the need to administer the compound, can potentially have many
advantages in drug development and in the safety testing of industrial
chemicals where dosing volunteers is often unacceptable.
Methods
D.BRUCE CAMPBELL 45
A meta-analysis of the papers related to this subject has been made from
those published over the last 20 years. Data before this have largely been
rejected due to the poor design of the studies or lack of analytical