title: PBPK Model for Atrazine and Its Chlorotriazine Metabolites in Rat and Human.
abstract: The previously-published physiologically based pharmacokinetic model for atrazine (ATZ), deisopropylatrazine (DIA), deethylatrazine (DEA), and diaminochlorotriazine (DACT), which collectively comprise the total chlorotriazines (TCT) as represented in this study, was modified to allow for scaling to humans. Changes included replacing the fixed dose-dependent oral uptake rates with a method that represented delayed absorption observed in rats administered ATZ as a bolus dose suspended in a methylcellulose vehicle. Rate constants for metabolism of ATZ to DIA and DEA, followed by metabolism of DIA and DEA to DACT were predicted using a compartmental model describing the metabolism of the chlorotriazines by rat and human hepatocytesin vitro Overall, the model successfully predicted both the 4-day plasma time-course data in rats administered ATZ by bolus dose (3, 10, and 50 mg/kg/day) or in the diet (30, 100, or 500 ppm). Simulated continuous daily exposure of a 55-kg adult female to ATZ at a dose of 1.0 µg/kg/day resulted in steady-state urinary concentrations of 0.6, 1.4, 2.5, and 6.0 µg/L for DEA, DIA, DACT, and TCT, respectively. The TCT (ATZ + DEA + DIA + DACT) human urinary biomonitoring equivalent concentration following continuous exposure to ATZ at the chronic point of departure (POD = 1.8 mg/kg/day) was 360.6 μg/L.
authors.affiliation: *The Hamner Institutes for Health Sciences, Center for Human Health Assessment, Research Triangle Park, North Carolina 27709-2137; jcampbell@ramboll.com.
authors.forename: Jerry L
authors.initials: JL
authors.lastname: Campbell
authors.affiliation: *The Hamner Institutes for Health Sciences, Center for Human Health Assessment, Research Triangle Park, North Carolina 27709-2137;
authors.forename: Melvin E
authors.initials: ME
authors.lastname: Andersen
authors.affiliation: Syngenta Crop Protection, LLC, Greensboro, North Carolina 27419-8300;
authors.forename: Paul M
authors.initials: PM
authors.lastname: Hinderliter
authors.affiliation: Syngenta Crop Protection, LLC, Greensboro, North Carolina 27419-8300;
authors.forename: Kun Don
authors.initials: KD
authors.lastname: Yi
authors.affiliation: Pastoor Science Communications, LLC, Greensboro, North Carolina 27455-3415.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Pastoor
authors.affiliation: Syngenta Crop Protection, LLC, Greensboro, North Carolina 27419-8300;
authors.forename: Charles B
authors.initials: CB
authors.lastname: Breckenridge
authors.affiliation: *The Hamner Institutes for Health Sciences, Center for Human Health Assessment, Research Triangle Park, North Carolina 27709-2137;
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Clewell
mesh_terms: D065567:Absorption, Physiological; D000284:Administration, Oral; D000818:Animals; D001280:Atrazine / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D014018:Tissue Distribution; D014227:Triazines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
chemical_list: D014227:Triazines; C060537:chlortriazine; D001280:Atrazine
keywords: atrazine; chlorotriazines; metabolism PBPK model; pharmacokinetics; risk assessment.