The Impact of Pesticides - Academy Publish

metabolite of phthalates, such that urinary background levels may be relatively highin some instances. Conversely, PI is a specific biomarker of exposure to folpet,stable in urine and easily measurable in blood and urine (Barr et al., 2002; Canal-Raffin et al., 2008; Berthet et al., 2011d).To describe and better understand the toxicokinetics of folpet and its ringmetabolites in humans, Heredia-Ortiz et al. (2011) developed models to describe thekinetics of either PI or PA eq (Figure 6B). Only the pathway leading to the formationof the PI and PA eq (i.e. the sum of PI, PAA and PA metabolites) biomarkers ofexposure was modeled. Conceptual representations and parameters values werebased on the human time-course data in volunteers orally and dermally exposed tofolpet (Berthet et al., 2011a, b) and available published metabolism data on folpet(Gordon et al., 2001; Gordon, 2010). Specific models were derived to represent thetime courses of PI and PA eq , given the differences in the kinetics of these twobiomarkers. To simulate the kinetics of PI specifically, PAA and PA wereconsidered as non-observed metabolites whereas to simulate the kinetics of PA eq , PI,PAA and PA compartments were lumped.In the models, input doses per unit of time, bioavailable at each site of absorption,the skin, the respiratory tract and the GI tract, were represented. Distinct GIcompartments were used to simulate folpet in the GI after oral exposure as well asthe almost instantaneously generated PI. Skin compartments were divided intoepidermis and dermis compartments to simulate the kinetics of PI following dermalexposure while the dermis was considered in equilibrium with blood in the modelfor PA eq . As for captan, inhalation exposures were modeled by direct inputs to theblood compartment and instant fragmentation at the N-S link, and accumulation intissues was considered negligible (Berthet et al., 2011a, b). Furthermore,compartments were considered to describe the body burden of PI, PAA, PA andexcretion in urine.Using these kinetic models, BRVs for PI and PA eq in 24-h urine collections werederived using a RfD abs established from the chronic oral RfD of 0.09 mg/kg bw/daysuggested by the U.S. EPA (1999b). This RfD is based on observed skin andstomach damaged cells in rats exposed at 35 mg/kg and on a NOEL of 9 mg/kg perday to which a safety factor of 100 was applied (EPA, 1999b). As a conservativescenario, the oral absorption fraction was set to be 1, such that the RfD abs wasconsidered equal to the exposure RfD. Following model simulations of a dermalexposure to the value of the RfD abs , the resulting BRVs obtained in 24-h urinecollections were 36.6 pmol/kg bw for PI and 32.0 nmol/kg bw for PA eq .To obtain an indication of the risk associated with exposure to folpet in workers,observed maximum daily amounts of PI and PA eq in the urine of workers followingtrimming and spraying activities over 3-7 days were compared to the proposed BRVin 24-h urine collections (Berthet et al., 2011e). The results show that in most cases,studied workers had maximum daily excretions exceeding the proposed referencevalues for PI regardless of the activity, while urinary values were below the PA eqBRV for all workers except one. To date, there is no other available study inworkers exposed to folpet to compare these reference values.Overall, as presented in Table 2, BRV values determined for THPI and PA eq withthe modeling approach are in the same range as those proposed for biomarkers ofOPs and carbaryl exposure in 24-h urine collections. Conversely, PI value is lower,AcademyPublish.org - The Impact of Pesticides118