title: The use of in vitro testing to refine cumulative assessment groups of pesticides: The example of teratogenic conazoles.
abstract: The most relevant issues in cumulative risk assessment (CRA) are the identification of cumulative assessment groups and the hypothesis of dose-additivity, at relevant human exposures. In vitro methods can provide meaningful data to help solving those issues. Integration of in vitro studies, selected in vivo studies, and PBPK modeling for teratogenic conazoles confirmed that in vitro studies may give results in a cheaper and faster fashion. In particular, in vitro studies with explanted rat embryos provided support for dose-additivity for conazoles causing cranio-facial malformations. Although this could not be immediately quantitatively transferred to the in vivo situation, they provided indication on how to conduct targeted in vivo studies. In addition, by means of PBPK modeling, it was possible to estimate the dose in humans associated with a defined teratogenic risk and also to conclude that for cumulative risk assessment only exposures occurring within a short period of time (a day or less) need to be cumulated. Although PBPK modeling cannot be widely applied, at least in the short term, it should be considered if available. It is recommended to incorporate in vitro testing and PBPK modeling, whenever available and feasible in the process of risk assessment, particularly of CRA.
authors.affiliation: Department of Biomedical and Clinical Sciences, University of Milano, Italy; International Centre for Pesticides and Health Risks Prevention (ICPS), Luigi Sacco Hospital, Milano, Italy. Electronic address: angelo.moretto@unimi.it.
authors.forename: Angelo
authors.initials: A
authors.lastname: Moretto
authors.affiliation: Department of Biosciences, University of Milano, Italy. Electronic address: francesca.direnzo@unimi.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Di Renzo
authors.affiliation: Department of Biosciences, University of Milano, Italy. Electronic address: erminio.giavini@unimi.it.
authors.forename: Erminio
authors.initials: E
authors.lastname: Giavini
authors.affiliation: International Centre for Pesticides and Health Risks Prevention (ICPS), Luigi Sacco Hospital, Milano, Italy. Electronic address: francesca.metruccio@icps.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Metruccio
authors.affiliation: Department of Biosciences, University of Milano, Italy. Electronic address: elena.menegola@unimi.it.
authors.forename: Elena
authors.initials: E
authors.lastname: Menegola
mesh_terms: D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D019465:Craniofacial Abnormalities / Q000139:chemically induced*; D004305:Dose-Response Relationship, Drug; D004477:Ectogenesis / Q000187:drug effects; D046149:Embryo Culture Techniques; D004622:Embryo, Mammalian / Q000187:drug effects*; D005260:Female; D005659:Fungicides, Industrial / Q000008:administration & dosage / Q000633:toxicity; D006801:Humans; D051379:Mice; D015233:Models, Statistical; D009994:Osmolar Concentration; D010575:Pesticides / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D018570:Risk Assessment; D013723:Teratogens / Q000633:toxicity*; D023382:Toxicity Tests, Acute; D066007:Toxicokinetics; D014230:Triazoles / Q000008:administration & dosage / Q000633:toxicity*
chemical_list: D005659:Fungicides, Industrial; D010575:Pesticides; D013723:Teratogens; D014230:Triazoles
keywords: Extrapolation; Grouping; Modeling; Quantitative; Risk assessment