PBPK-Based Probabilistic Risk Assessment for Total Chlorotriazines in Drinking Water.

Atrazine (6-chloro-N2-ethyl-N4-isopropyl-1,3,5-triazine-2,4-diamine; CAS No. 1912-24-9) is a herbicide used for preplant and early postplant control of broadleaf weeds and some grasses in corn and sorghum grown in the continental United States (Bridges, 2008). The chlorotriazines (atrazine, simazine, propazine, and terbuthylazine) continue to play an important role in weed control and the management of weed resistance in the United States, Europe (terbuthylazine), and Australia. However, because of the potential for runoff from treated fields into surface water, as well as a moderate mobility that permits the chlorotriazines to reach groundwater (Thurman and Scribner, 2008), concerns have been raised about risks associated with human exposure to this class of chemicals. Hazard profiles have been well characterized for atrazine (ATZ) and its chlorotriazine metabolites deethylatrazine (DEA), deisopropylatrazine (DIA), and diaminochlorotriazine (DACT) (Breckenridge et al., 2010). The data support the conclusion that the chlorotriazines share a common mechanism of toxicity (USEPA, 2002). Human risk was assessed in this study by estimating the cumulative exposure to total chlorotriazines (TCT) appearing in drinking water and then calculating distributions of margins of exposure (MOEs), based on sensitive toxicological points of departure (POD). Detailed evaluations of the endocrine mode of action of the triazines have been published (Cooper et al., 2007; Simpkins et al., 2011), and epidemiological evidence of associations between triazine exposure and various cancers and reproductive outcomes have been reviewed elsewhere (Boffetta et al., 2013; Goodman et al., 2014; Sathiakumar et al., 2011). The most sensitive effect of ATZ in animal studies is the suppression of the preovulatory luteinizing hormone (LH) surge in female Sprague Dawley (SD) rats administered ATZ in the diet for 6 months (Simpkins et al., 2011). The no-observed-effect level (NOEL) from this study (NOEL = 1.8 mg/kg/d) has been used by the United States Environmental Protection Agency (USEPA) (2006) and the World Health Organization (WHO) (2010) to establish the POD for the chlorotriazines and to evaluate intermediate term and lifetime risks of exposure to ATZ and TCT. The USEPA concluded that using the POD based on LH surge suppression in neuroendocrinologically aged, female SD rats was conservatively protective of human health (USEPA, 2013). Shorter-duration administration of ATZ by gavage to adult female SD (Minnema, 2001), Wistar (McMullin et al., 2004), or Long Evans (LE) rats (Cooper et al., 2007) resulted in NOELs higher than the levels observed following chronic dietary administration (Simpkins et al., 2011). Although the USEPA has officially maintained the uncertainty factor (UF) for calculating the chronic reference dose and the maximum contaminant level (MCL) for ATZ in drinking water at 1000, the WHO used a UF = 100 for calculating the acceptable daily intake of ATZ. It is likely that as new standards are set to regulate exposure to TCT, the UF will be reduced, especially if pharmacokinetic models are used to assess risk. It is generally accepted that when physiologically based pharmacokinetic (PBPK) models are used to scale rodent doses to man, there is no need to employ a 2.5- to 3-fold scaling factor that traditionally is used to extrapolate the administered dose in animals to man (Renwick and Lazarus, 1998; WHO, 2005). Bolus dose (BD) administration of ATZ to young adult female SD rats daily for 4 days resulted in a NOELBD of 10 mg/kg/d. A POD of 2.56 mg/kg/d, calculated for LH suppression in LE rat based on the 95th-percentile lower bound benchmark dose (BMDL) (Cooper et al., 2010; USEPA, 2011a), was also used in this assessment. A distributed dose (DD), NOEL (NOELDD) of 50 mg/kg/d, also evaluated in this assessment, was from a study where ATZ was administered in the diet over 4 successive days (Foradori et al., 2014). The 5-fold difference in NOELs following bolus versus DD administration is likely explained by rapid absorption and short plasma clearance half-lives of ATZ and its chlorotriazine metabolites following oral dosing. BD administration results in higher peak plasma TCT concentrations than when the dose is distributed over time. The distributed-dosing scenario more closely resembles potential human exposure to the chlorotriazines in drinking water, where the daily dose is temporally distributed over the day. This study provides a comprehensive risk assessment for the chlorotriazines in drinking water by calculating MOEs from chemograph-based human exposure profiles and a conservative estimate of the human NOEL/POD. Exposure was determined by using TCT chemographs along with daily surveys of individual human water consumption (Barraj et al., 2009). The resulting temporal pattern of human exposure was converted to estimated, time-dependent, internal human plasma TCT concentrations using a PBPK model (Campbell et al., 2016). The human POD was established by using the PBPK model to convert an administered TCT-POD dose to the TCT-POD plasma concentration (Figure 1). The ratio of the model-derived human TCT concentration in plasma, at the selected POD, to the human TCT plasma resulting from exposure to TCT in drinking water was calculated for each scenario. Sensitivity analyses were conducted to evaluate the impact of changes in PBPK model parameters and risk assessment input variables, including chemographic characteristics (days within a year, season, and location), human factors (age, gender, and water consumption), selection of the NOEL/POD, water sampling frequency, and methods used to interpolate between measured TCT concentrations. Overall, the results indicate that there were acceptable MOEs for all scenarios evaluated. FIG. 1 Schematic representation of the use of a PBPK model to characterize human exposure (human internal dose) and risk (MOE).