title: ILSI/HESI maternal toxicity workshop summary: maternal toxicity and its impact on study design and data interpretation.
abstract: Workshops on maternal toxicity were held at the annual Society of Toxicology, Teratology Society, and European Teratology Society meetings in 2009. Speakers presented background information prior to a general discussion on this topic. The following recommendations/options are based on the outcome of the discussions at the workshops: 1. A comprehensive evaluation of all available data from general toxicity studies, range-finding Developmental and Reproductive Toxicology (DART) studies, class effects, structure-activity relationships, exposure studies, etc. is essential for appropriate dose selection for definitive DART studies. The intent is to avoid marked maternal toxicity leading to mortality or decreased body weight gains of greater than 20% for prolonged periods. (a) Evaluate alternative endpoints for dose selection and data interpretation (e.g., target tissue effects and pharmacology) for biotherapeutics. (B) Evaluate additional maternal parameters based on effects and/or target organs observed in short-term (e.g., 2- or 4-week) general toxicity studies. 2. Evaluate all available data to determine a cause-effect relationship for developmental toxicity. (a) Conduct a pair-feeding/pair-watering study as a follow-up. (b) Evaluate individual data demonstrating maternal toxicity in the mother with adverse embryo-fetal outcomes in the litter associated with the affected mother. (c) Conduct single-dose studies at increasing doses as a complement to conventional embryo-fetal toxicity studies for certain classes of compounds that affect the hERG channel. 3. Support statements that embryo-fetal effects are caused by maternal toxicity and/or exaggerated pharmacology, especially for malformations. (a) Provide mechanistic or other supporting data. (b) Establish the relevance of the DART findings in animals for human exposures. Birth Defects Res (Part B) 92:36-51, 2010. © 2011 Wiley-Liss, Inc.
authors.affiliation: Department of Disposition, Safety and Animal Research-Preclinical Safety, sanofi-aventis US Inc., Bridgewater, New Jersey 08807-0800, USA. bruce.beyer@sanofi-aventis.com
authors.forename: Bruce K
authors.initials: BK
authors.lastname: Beyer
authors.forename: Neil
authors.initials: N
authors.lastname: Chernoff
authors.forename: Bengt R
authors.initials: BR
authors.lastname: Danielsson
authors.forename: Karen
authors.initials: K
authors.lastname: Davis-Bruno
authors.forename: Wafa
authors.initials: W
authors.lastname: Harrouk
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Hood
authors.forename: Gemma
authors.initials: G
authors.lastname: Janer
authors.forename: Ulla Wändel
authors.initials: UW
authors.lastname: Liminga
authors.forename: James H
authors.initials: JH
authors.lastname: Kim
authors.forename: Meredith
authors.initials: M
authors.lastname: Rocca
authors.forename: John
authors.initials: J
authors.lastname: Rogers
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Scialli
mesh_terms: D000818:Animals; D001835:Body Weight; D047108:Embryonic Development; D005260:Female; D005333:Fetus / Q000473:pathology; D006801:Humans; D018811:Maternal Exposure; D051379:Mice; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000473:pathology; D011817:Rabbits; D051381:Rats; D012107:Research Design; D013223:Statistics as Topic; D018675:Toxicity Tests / Q000379:methods*