title: Threshold of toxicological concern (TTC) for developmental and reproductive toxicity of anticancer compounds.
abstract: Pharmaceutical companies develop specialized therapies to treat late stage cancer. In order to accelerate life-saving treatments and reduce animal testing, compounds to treat life-threatening malignancies are allowed modified requirements for preclinical toxicology testing. Limited data packages in early drug development can present product quality challenges at multi-product manufacturing facilities. The present analysis established an endpoint-specific threshold of toxicological concern (TTC) for developmental and reproductive toxicity (DART) for anticancer compounds. A comprehensive database was created consisting of over 300 no-observed adverse effect levels (NOAELs) for DART of 108 anticancer compounds. The 5th percentile NOAEL for developmental and reproductive toxicity was 0.005 mg/kg/day (300 μg/day), resulting in a human exposure threshold of 3 μg/day assuming standard uncertainty factors and a 60 kg human bodyweight. The analysis shows this threshold is protective for developmental and reproductive toxicity of highly potent groups of anticancer compounds. There were similar TTC values calculated for direct-acting and indirect-acting anticancer compounds.
authors.affiliation: MedImmune, One MedImmune Way, Gaithersburg, MD 20878, USA; Colorado State University, Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Ft. Collins, CO 80523, USA. Electronic address: stanardb@medimmune.com.
authors.forename: Brad
authors.initials: B
authors.lastname: Stanard
authors.affiliation: Amgen, Inc., One Amgen Center Drive, MS 28-1A, Thousand Oaks, CA 91360, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Dolan
authors.affiliation: Colorado State University, Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Ft. Collins, CO 80523, USA.
authors.forename: William
authors.initials: W
authors.lastname: Hanneman
authors.affiliation: Colorado State University, Department of Environmental and Radiological Health Sciences, College of Veterinary Medicine and Biomedical Sciences, Ft. Collins, CO 80523, USA.
authors.forename: Marie
authors.initials: M
authors.lastname: Legare
authors.affiliation: Amgen, Inc., One Amgen Center Drive, MS 28-1A, Thousand Oaks, CA 91360, USA.
authors.forename: Joel P
authors.initials: JP
authors.lastname: Bercu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D047108:Embryonic Development / Q000187:drug effects; D047109:Fetal Development / Q000187:drug effects; D006801:Humans; D012098:Reproduction / Q000187:drug effects; D018570:Risk Assessment / Q000379:methods*; D018675:Toxicity Tests
chemical_list: D000970:Antineoplastic Agents
keywords: Acceptable Daily Exposure (ADE); Anticancer; Antineoplastic; Developmental toxicity; Direct-acting; Indirect-acting; Permitted Daily Exposure (PDE); Reproductive toxicity; Threshold of toxicological concern (TTC)