The Impact of Pesticides - Academy Publish

exposure scenarios on the basis of the time course of urinary biomarkers inindividuals and 2) to reconstruct daily absorbed doses from biomarkers levelsmeasured in accessible sampled matrices.To describe the kinetics of a given pesticide and its metabolites in humans with suchapproach, the first step is the development of a mathematical model composed ofvarious linked compartments. This model is specific to the substance of interest andlinks amounts absorbed and their rate of absorption to excretion rates. Its purpose isto simulate essential biological features of the dynamics with a minimum number ofparameters to reproduce the measured urinary and blood time profiles of themolecule under study. The required degrees of freedom in the simulation aredetermined from direct best-fitting to experimental data on the time courses of thepesticide and its metabolites in accessible biological matrices (e.g. blood and urine).The conceptual representation of the general modeling of the kinetics of nonpersistentpesticides followed in past studies (Bouchard et al., 2003, 2005, 2006,2008; Gosselin et al., 2004; Heredia-Ortiz et al., 2011; Heredia-Ortiz and Bouchard,2011) is depicted in Figure 1. Compartments represent burdens, on a mole basis, ofthe pesticide in the body or cumulative excretion of metabolites as a function oftime. Variations in time in compartment burdens are described mathematically bysystems of differential equations (See Table 1 for description of differentialequations). Most effective toxicokinetic models are based on first-order transferrates which lead to a linear set of first-order ordinary differential equations. By firstorderprocesses, it implies that the rate of change in the amounts in a givencompartment is proportional to the amounts in the compartment at all times.Therefore, the rates of change in the amounts of a substance in a given compartmentare described mathematically as the difference between compartment rates of uptakeand loss. Exchange rates between compartments, described by arrows, representeither the physical transfer of the same substance or the transfer (on a mole to molebasis) through the biotransformation of the studied toxic substance into itsmetabolites or primary metabolites into derivatives. This kind of models is notrestrained to be linear. Any of the rates presented could be changed to take intoaccount any non-lineal mechanism like saturation phenomena (not just anenzymatic-like one, i.e. Michaelis-Menten kinetics), storage or protein binding.The kinetics of the studied pesticide and its experimentally relevant metabolites aremodeled for different routes-of-exposure, for example oral, dermal and inhalation.The input doses per unit of time, bioavailable at each site of absorption, the skin, therespiratory tract (RT) and the gastrointestinal tract (GI), are described as g dermal (t),g inh (t) and g oral (t), respectively. They are linked to their specific input compartment,which represents the amount of pesticide available at each site of absorption andgenerally illustrated by the symbols D(t), RT(t) and GI(t). A blood compartment(B(t)) is then used to describe the body burden of the pesticide in blood and intissues in dynamical equilibrium with blood, i.e. tissues that rapidly reach andmaintain a fixed ratio with blood. Another compartment is sometimes added toregroup storage tissue burdens of pesticides that are slowly returned to blood.Metabolite specific compartments, that is a compartment for each metabolite orgroups of metabolites (specific or not to the studied pesticide) are added to representmetabolite burdens in blood and in tissues in dynamic equilibrium with blood (e.g.M x (t), M y (t), …). Similarly, different excretion compartments are introduced torepresent cumulative amounts of the urinary metabolites (e.g. U x (t), U y (t), …) orAcademyPublish.org - The Impact of Pesticides108