title: Dose-response relationships of rat fetal skeleton variations: Relevance for risk assessment.
abstract: In developmental toxicity studies, skeleton abnormalities found in fetuses at term are classified as variations or malformations. The relevance of skeleton variations for human risk assessment, however, is a controversial issue. This paper is a contribution to the discussion on the interpretation of fetal skeleton variations in the context of risk assessment. Dose-response relationships of skeleton variations and malformations induced by three antineoplastic drugs (FUDR: 5-fluoro-2'-deoxyuridine, HU: hydroxyurea and 6-MPr: 6-mercaptopurine-riboside) were evaluated. FUDR (0, 3, 14, 25, 35, 45, 55 and 65mg/kg body wt sc) and HU (0, 250, 300, 350, 400, 450, 500 and 550mg/kg body wt ip) were administered to rats on gestation day 11 (GD 11) while 6-MPr (0, 3, 7, 10 and 14mg/kg body wt sc) was given on GD 11, or on GD 12. Caesarean sections were performed on GD 21 and all fetuses were cleared and stained with alizarin red S for skeleton examination. Drugs given on GD 11 increased the incidence of thoracic and lumbar vertebra (dumbbell-shaped and bipartite ossification center (o.c.) and sternum (misaligned sternebrae) variations in a dose-dependent manner. Occurrence of zygomatic bone fused with maxilla (a variation in our rats) was also increased by HU and 6-MPr (GD 11) but it was not altered by FUDR. Spontaneous occurrence of wavy ribs was reduced by all treatments. Malformations such as cleft palate, tympanic bone absent and tibia absent were also increased in a dose-dependent manner by the three compounds. No observed effect levels (NOEL) for variations, irrespective of the compound administered, were generally lower than NOELs for malformations. In the discussion, we supported the view that any dose-related increase in the incidence of variations should be taken into account for determination of NOELs in routine studies. Increased occurrences of skeleton variations in term fetuses are also to be considered in risk assessment, unless experimental evidence exists that a particular change has no detrimental effect on the animal survival or health after birth or that it does not occur in humans.
authors.affiliation: Institute of Clinical Pharmacology and Toxicology, Charité University Medical School Berlin, Garystrabetae 5, 14195 Berlin, Germany. ibrahim.chahoud@charite.de
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Chahoud
authors.forename: Francisco J R
authors.initials: FJ
authors.lastname: Paumgartten
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001842:Bone and Bones / Q000002:abnormalities* / Q000187:drug effects / Q000196:embryology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005467:Floxuridine / Q000633:toxicity; D006918:Hydroxyurea / Q000633:toxicity; D018811:Maternal Exposure / Q000009:adverse effects*; D015122:Mercaptopurine / Q000633:toxicity; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000970:Antineoplastic Agents; D005467:Floxuridine; D015122:Mercaptopurine; D006918:Hydroxyurea