Toxicology of Industrial Compounds

4
Sizing up the Problem of Exposure Extrapolation:
New Directions in Allometric Scaling
D.BRUCE CAMPBELL
Director International Scientific Affairs, Servier Research and
Development, Slough
Introduction
The evaluation of the safety of industrial chemicals requires the
administration of a range of doses to test animals over periods of time and
the extrapolation in some meaningful way to man. Various risk assessment
models have been suggested which attempt to measure an uncertainty or
safety factor which can be used to extrapolate to man to obtain an
acceptable daily intake (ADI) (Dourson and Stara, 1983). Other
approaches are also used, such as benchmark dose, the smallest dose which
produces a statistical increase in toxicity over the background level (Crump,
1984), or more frequently the LOEL, the lowest observed dose which
produces an adverse effect, and NOEL, the highest dose at which no
adverse effect is observed. There are difficulties in the interpretation of
these exposure margins since there is often little information on: (1) the
slope or intensity of the effect, (2) species differences in the sensitivity, (3)
the possibility of cumulative or irreversible toxicities, etc. But perhaps the
most important weakness in these estimates is the lack of knowledge of the
actual circulating levels of the chemical(s) in the different species. This
problem is particularly pertinent for industrial chemicals and environmental
pollutants where it may be unethical to administer doses of these
compounds to volunteers which are sufficiently high to measure the
kinetics. It is of special concern since it is well known that there are large
interspecies differences in the clearance of chemicals and that comparison of
doses in animals, expressed simply in terms of mg kg −1 , provides little
information as to the actual exposure likely to occur. This is not surprising
since small animals have relatively faster blood flow and larger organs than
man when expressed as a percentage of body weight, and consequently
clearance is more rapid and circulating levels of the administered
compound are lower than could be expected during toxicity testing
(Campbell and Ings, 1988).
However since most mammals share similar physiological and
biochemical actions these differences in physiological rates and sizes for