Comparison of non-linear and linear models for estimating haemoglobin adduct stability

According to the kinetic theory for the build-up and elimination of haemogl obin (Hb) adducts, unstable Hb adducts are simultaneously eliminated by zer o-order Hb turnover and first-order chemical instability. Thus, the elimina tion of unstable Hb adducts is nonlinear with respect to time. Nonetheless, many studies of Hb adduct stability have characterized the elimination of Hb adducts using linear zero-order or linear first-order models. This paper demonstrates the use of non-linear regression to estimate the first-order rate constant of Hb adduct instability (k) using data on the elimination of Hb adducts in rats dosed with benzene or ortho-toluidine. Results obtained using non-linear regression models are compared with results from the more commonly employed zero- and first-order linear models. It is shown that ex posure estimates based on measured levels of unstable Hb adducts can be sev erely biased if zero- order turnover is assumed. Furthermore, based on publ ished data, estimates of k are subject to estimated relative biases in the range of -4 % to 96 % when first-order linear models are used to characteri ze Hb adduct instability.