Distributions of Individual Susceptibility among Humans for Toxic Effects: How Much Protection Does the Traditional Tenfold Factor Provide for What Fraction of Which Kinds of Chemicals and Effects?

Abstract

A significant data base has been assembled on human variability in parameters representing a series of steps in the pathway from external exposure to the production of biological responses: contact rate (e.g., breathing rates/body weight, fish consumption/body weight); uptake or absorption (mg/kg)/intake or contact rate; general systemic availability net of first pass elimination and dilution; systemic elimination or half-life; active site availability/general systemic availability; physiological parameter change/active site availability; functional reserve capacity--change in baseline physiological parameter needed to pass a criterion of abnormal function or exhibit a response. This paper discusses the current results of analyzing these data to derive estimates for distributions of human susceptibility to different routes of exposure and types of adverse effects. The degree of protection is tentatively evaluated by projecting the incidences of effects that would be expected for a tenfold lowering of exposure from a 5% incidence level if the population distribution of susceptibility were truly log-normal out to the extreme tails, and if the populations, chemicals, and responses that gave rise to the underlying data were representative of the cases to which traditional uncertainty factor is applied. The results indicate that, acting by itself, a tenfold reduction in dose from a 5% effect level is associated with effect incidences ranging from slightly less than one in ten thousand, for a median chemical/response, to a few per thousand, for chemicals and responses that have greater human interindividual variability than 19 out of 20 typical chemicals/responses. In practice, for many of the cases where the traditional tenfold factor is applied, additional protection is provided by other uncertainty factors. Nevertheless, the results generate some reason for concern that current application of traditional safety or uncertainty factor approaches may allow appreciable incidences of responses in some cases.

Introduction to Drinking Water Risk Assessment

“…That is, if one determines the average dose that is without adverse effects in a typical small group of test subjects and divides that number by 10, this dose should be without effect in any person within the entire population. Evaluations of this with real data, such as data on pharmaceutical effect levels (Hattis et al, 1999) or drug half-lives (Ginsberg et al, 2002), show that a factor of 10 is adequate to encompass most of the variability among adults but is not necessarily adequate to protect infants and children.…”

Considerations for Improving High to Low Dose Extrapolation for Regulatory Risk Assessment

“…The extent that interspecies differences in lethality would be quantitatively similar for other endpoints such as neurotoxicity or IQ loss has not been explored. Human heterogeneity has been quantified by considering its components such as uptake, metabolism, and pharmacodynamics (Hattis et al 1999). Human variability has been represented by unimodal and smooth distributions calculated from small sample sizes that do not fully account for polymorphisms and other susceptibility influences and may miss distinct highly sensitive populations.…”

Human Milk Biomonitoring Data: Interpretation and Risk Assessment Issues

“…Most comprehensive studies suggest that a high percentage of the population, including children, is protected by using a 10-fold uncertainty factor for human variability or by using a 3.16-fold variability each for toxicokinetic and toxicodynamic variability (Renwick & Lazarus, 1998;Hattis et al, 1999aHattis et al, , 1999b.…”