Human variability in susceptibility to toxic chemicals--a preliminary analysis of pharmacokinetic data from normal volunteers.

The tenfold "uncertainty" factor traditionally used to guard against human interindividual differences in susceptibility to toxicity is not based on human observations. To begin to build a basis for quantifying an important component of overall variability in susceptibility to toxicity, a data base has been constructed of individual measurements of key pharmacokinetic parameters for specific substances (mostly drugs) in groups of at least five healthy adults. 72 of the 101 data sets studied were positively skewed, indicating that the distributions are generally closer to expectations for log-normal distributions than for normal distributions. Measurements of interindividual variability in elimination half-lives, maximal blood concentrations, and AUC (area under the curve of blood concentration by time) have median values of log10 geometric standard deviations in the range of 0.11-0.145. For the median chemical, therefore, a tenfold difference in these pharmacokinetic parameters would correspond to 7-9 standard deviations in populations of normal healthy adults. For one relatively lipophilic chemical, however, interindividual variability in maximal blood concentration and AUC was 0.4--implying that a tenfold difference would correspond to only about 2.5 standard deviations for those parameters in the human population. The parameters studied to date are only components of overall susceptibility to toxic agents, and do not include contributions from variability in exposure- and response-determining parameters. The current study also implicitly excludes most human interindividual variability from age and illness. When these other sources of variability are included in an overall analysis of variability in susceptibility, it is likely that a tenfold difference will correspond to fewer standard deviations in the overall population, and correspondingly greater numbers of people at risk of toxicity.