title: Evaluation of developmental toxicity studies of glyphosate with attention to cardiovascular development.
abstract: The herbicide glyphosate has undergone multiple safety tests for developmental toxicity in rats and rabbits. The European Commission's 2002 review of available glyphosate data discusses specific heart defects observed in several individual rabbit developmental toxicity studies, but describes the evidence for a potential causal relationship as equivocal. The present assessment was undertaken to analyze the current body of information generated from seven unpublished rabbit studies in order to determine if glyphosate poses a risk for cardiovascular malformations. In addition, the results of six unpublished developmental toxicity studies in rats were considered. Five of the seven rabbit studies (dose range: 10-500 mg/kg/day) were GLP- and testing guideline-compliant for the era in which the studies were performed; a sixth study predated testing and GLP guidelines, but generally adhered to these principles. The seventh study was judged inadequate. In each of the adequate studies, offspring effects occurred only at doses that also caused maternal toxicity. An integrated evaluation of the six adequate studies, using conservative assumptions, demonstrated that neither the overall malformation rate nor the incidence of cardiovascular malformations increased with dose up to the point where severe maternal toxicity was observed (generally ≥150 mg/kg/day). Random occurrences of cardiovascular malformations were observed across all dose groups (including controls) and did not exhibit a dose-response relationship. In the six rat studies (dose range: 30-3500 mg/kg/day), a low incidence of sporadic cardiovascular malformations was reported that was clearly not related to treatment. In summary, assessment of the entire body of the developmental toxicity data reviewed fails to support a potential risk for increased cardiovascular defects as a result of glyphosate exposure during pregnancy.
authors.affiliation: Exponent Inc, Alexandria, VA 22314, USA.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Kimmel
authors.forename: Carole A
authors.initials: CA
authors.lastname: Kimmel
authors.forename: Amy L
authors.initials: AL
authors.lastname: Williams
authors.forename: John M
authors.initials: JM
authors.lastname: DeSesso
mesh_terms: D000818:Animals; D018376:Cardiovascular Abnormalities / Q000453:epidemiology / Q000209:etiology*; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000187:drug effects; D047108:Embryonic Development / Q000187:drug effects*; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D005998:Glycine / Q000031:analogs & derivatives* / Q000633:toxicity; D006540:Herbicides / Q000633:toxicity*; D006801:Humans; D018811:Maternal Exposure; D019055:No-Observed-Adverse-Effect Level; D011247:Pregnancy; D011817:Rabbits; D051381:Rats; D018570:Risk Assessment; D018675:Toxicity Tests; D000097797:Glyphosate
chemical_list: D005998:Glycine; D006540:Herbicides; D000097797:Glyphosate