Differences in individual susceptibility to toxic effects of chemicals determine the dose-response relationship and consequences of setting exposure standards.
The dose-response curve obtained in toxicity testing is a mirror image of the susceptibility distribution in the treated population, i.e. it follows increasing tolerance of the individuals to the adverse effects of the chemical under investigation. Defining a dose as a maximum tolerated exposure level, therefore, splits the 'public' into two groups, those who are protected and those who are not, and the position of the exposure standard in the dose-response curve defines the percent unprotected. This understanding is particularly relevant for genotoxic carcinogenesis, for which the assumption of a linear dose-response relationship at low dose is often made. In this case, reduction of the dose by a given factor reduces the percent unprotected by the same factor, and the percentage will never be zero. These considerations have two major consequences. First, the hypothetical cancer risk calculated from the exposure standard must be put in relation to a background cancer risk and its modulation by generally accepted lifestyle factors. Second, knowledge of the factors that modulate and determine an individual susceptibility is the key to defining particularly susceptible subpopulations and individuals. The search for and elimination of such cofactors that render individuals more susceptible might be more appropriate than a general reduction of an exposure standard.
Lutz
Werner K
WK
Department of Toxicology, University of Würzburg, Versbacher Strasse 9, D-97078 Wurzburg, Germany. lutz@toxi.uni-wuerzburg.de
D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004781:Environmental Exposure / Q000592:standards*; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D006801:Humans; D016014:Linear Models; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000139:chemically induced / Q000235:genetics / Q000517:prevention & control; D019055:No-Observed-Adverse-Effect Level; D018570:Risk Assessment; D012449:Safety / Q000592:standards; D015262:Xenobiotics / Q000008:administration & dosage* / Q000633:toxicity*
D002273:Carcinogens; D015262:Xenobiotics