The Impact of Pesticides - Academy Publish

exposed to captan (Berthet et al., 2011a, b). The model was also corroborated withthe volunteer data of Krieger and Thongsinthusak (1993) as well as experimental invivo kinetic data in animals (Seidler et al., 1971; DeBaun et al., 1974; Couch et al.,1977; van Welie et al., 1991; Fisher et al., 1992) along with other non-public resultssummarized in reviews on captan (Larsen, 1996; Wilkinson, 2003; EPA, 2004; Foodand Agriculture Organization of the United Nations (FAO), 2007; Gordon, 2010).An approach similar to the one used for OP insecticides and carbaryl has beenapplied to establish the conceptual representation of the model (Figure 6A). Themodel consists of specific inputs to describe captan bioavailable at each absorptionsite (GI tract, skin and respiratory tract); blood compartments to represent captanand the experimentally relevant THPI metabolite in blood and in tissues indynamical equilibrium with blood; excretion compartments to describe cumulativeamounts of THPI in urine and faeces, respectively. In the model, inhalation wassimulated by direct inputs to the blood compartment, given that captan is rapidlyabsorbed through the respiratory tract and this can be considered kinetically as analmost constant intravenous exposure. Furthermore, as a linear THPI elimination inblood of volunteers orally exposed to 1 mg/kg bw of captan was observed in thestudy of Berthet et al. (2011a), no storage compartment was added to represent anaccumulation in lipids or a binding to tissue proteins.Unlike OPs and carbamate insecticides, health effects induced by phthalimidefungicides in humans are not clearly characterized. Therefore, to determine a BRVfor urinary THPI, Heredia-Ortiz and Bouchard (2011) selected an absorbed dose(RfD abs ) corresponding to the chronic oral reference dose (RfD) of 0.125 mg/kgbw/day proposed by the U.S. EPA (EPA, 2004) on the basis of a rat study. An oralabsorption fraction of 1 was considered, such that the RfD abs was set equal to theexposure RfD. The RfD was derived from a NOAEL of 12.5 mg/kg bw/day in athree-generation reproduction study in rats to which a safety factor of 100 wasapplied. Following model simulations of a dermal exposure to the value of theRfD abs , the BRV obtained for workers in 24-h urine collections was 21.5 nmolTHPI/kg bw/day.Table 3 presents mean cumulative amounts of THPI in 24-h urine collections ofworkers exposed to captan following different activities in several studies (Winterlinet al., 1986; Verberk et al., 1990; de Cock et al., 1995; Krieger and Dinoff, 2000;Hines et al., 2008). These published values were found to be below the proposedBRV determined with the model and based on a conservative reference dose.FolpetAs captan, folpet metabolism is well documented in animals and in vitro studies(Chasseaud et al., 1974; Chasseaud et al., 1991; Gordon et al., 2001; Canal-Raffinet al., 2008; Gordon, 2010). Folpet is rapidly metabolized to phthalimide metabolite(PI) and thiosphogene, an unstable metabolite which reacts with cysteine orglutathione to form TTCA. PI is also rapidly hydrolyzed to phthalamic acid (PAA),and in turn to phthalic acid (PA). According to studies in rats exposed to folpetfollowing an oral, intratracheal, or intraperitoneal administration (Chasseaud et al.,1974; Chasseaud, 1980; Chasseaud et al., 1991; Canal-Raffin et al., 2008), PAA isthe main ring-metabolite (over 80%). However, this metabolite is a very unstablecompound in human urine and it is more convenient to transform PI and PAAmetabolites to PA in acid conditions, and to measure total PA equivalents (PA eq ) inurine as a biomarker of exposure (Berthet et al., 2011c). Nevertheless, PA is also aAcademyPublish.org - The Impact of Pesticides117