The Impact of Pesticides - Academy Publish

cyclohexene-1,2-dicarboximide, CAS 133-06-2) and folpet (N-[Trichloromethylthio]phthalimide, CAS 133-07-3). In humans, both fungicides wereinitially classified as probable human carcinogens (B2) by the (EPA, 1975, 1999b)based on an increased incidence of duodenum tumors in rodents chronically exposedto high doses by gavage. However, in 2004 captan classification changed to “notlikely” considering that the doses administered to mice were much higher than thoseencountered in occupational settings (EPA, 2004; Gordon, 2007). Both compoundsare also considered as sensitizers and strong irritants of the eyes, skin andrespiratory airways, but no systemic toxicity was reported (Hayes, 1982; Edwards etal., 1991; Trochimowicz et al., 1991; Tomlin, 1997; EPA, 1999b, 2004; Costa,2008; Gordon, 2010; ACGIH, 2011). Some studies also reported skin andrespiratory problems in workers exposed to captan or folpet (Burroughs and Hora,1982; Lisi et al., 1987; Guo et al., 1996). As a result, occupational guidelines werederived for captan, namely a TLV ® -TWA of 5 mg/m 3 (ACGIH, 2011), but none areavailable to date for folpet.Recently, BRVs were also proposed for captan and folpet metabolites using atoxicokinetic modeling approach (Heredia-Ortiz et al., 2011; Heredia-Ortiz andBouchard, 2011). More specifically, based on available toxicokinetic data (Kriegerand Thongsinthusak, 1993; Berthet et al., 2011a, b), two toxicokinetic models weredeveloped to allow a better assessment of the effect of the exposure route andtemporal scenario on the biomarkers kinetics of captan and folpet (Heredia-Ortiz etal., 2011; Heredia-Ortiz and Bouchard, 2011). These models were then used toreconstruct absorbed doses from biomarker data and define BRVs, or safe dailyurinary biomarker levels corresponding of an exposure dose limit for workers. Toillustrate the applicability of the general approach developed for OPs and carbamateinsecticides to other compound families, the examples of captan and folpet aredetailed below.CaptanToxicokinetic data on captan are well documented in in vivo studies in animalsusually exposed to the radiolabelled compound as well as in in vitro studies.According to these studies, captan is an unstable molecule in aqueous medium andin biological fluids when in contact with thiols. Gordon et al. (2001) estimated ahalf-life in the order of a second (0.97 s) following addition of C 14 -labelled captan(1 mg/L) to human blood. The first step in the metabolism of captan is the nonenzymaticbreakdown of N-S link to form a tetrahydrophthalimide (4,5-cyclohexene-1,2-dicarboximide; THPI) and a derivative of the trichloromethylthiogroup, namely thiocarbonyl chloride. The latter in turn reacts with thiols to formthiophosgene, a transient metabolite, which readily reacts with cysteine orgluthathione to form thiazolidine-2-thione-4-carboxylic acid (TTCA). Inbiomonitoring studies (EPA, 1975), measurement of THPI is favored to TTCA sinceit is more stable in biological matrices and TTCA is less specific, being also aurinary metabolite of carbon disulfide (Amarnath et al., 2001).In order to determine exposure and health risks in workers from amounts of urinarybiomarkers, Heredia-Ortiz and Bouchard (2011) developed a toxicokinetic model,which reproduces the time course of THPI biomarker in blood and urine fordifferent temporal scenarios (single, repeated intermittent or continuous exposures)and exposure routes (oral, dermal, respiratory). The determination of modelparameters was based on available published metabolism data (Gordon et al., 2001)along with the human time-course data collected in volunteers orally and dermallyAcademyPublish.org - The Impact of Pesticides116