Human Variability in Susceptibility to Toxic Chemicals— A Preliminary Analysis of Pharmacokinetic Data from Normal Volunteers

Abstract

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.

Development of a Physiologically-Based Pharmacokinetic Model of Trichloroethylene and Its Metabolites for Use in Risk Assessment

“…Pharmacokinetic and metabolic differences alone cannot explain the overall interindividual variation in susceptibility observed in exposed populations (173,180). Clearly there are other, less well understood interindividual differences, both acquired (due to environmental exposures or disease states) and inherited (due to genetic differences) that are also important determinants of the individual risk for development of toxicity from exposure to a chemical.…”

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“…However, advances in biochemistry and toxicology led scientists and regulators to realize that these two default factors would not cover the differences and the complexity of the wide range of metabolic fates and mechanisms of toxicity in laboratory species and in humans. Analyses were performed to investigate the validity of the assessment factors and to further refine them (Dourson and Stara 1983;Calabrese 1985;Hattis et al 1987;Renwick 1991Renwick , 1993Abdel-Rahman and Kadry 1995;Naumann and Weideman 1995;Renwick and Lazarus 1998;Burin and Saunders 1999). Notwithstanding these advancements, the original concept of an experimentally derived benchmark (e.g.…”

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“…bThe numbers are the ratios of the value of each parameter for the 95th percentile individual to the value of the parameter for the 5th percentile individual (see Figure 1 for illustration), based on the assumption that the values of the parameter are lognormally distributed (that is, the logarithms of the parameter values are normally distributed). cData from Hattis et al (21). dData from Hattis et al (22).…”