Vinclozolin: a feasibility and sensitivity study of the ILSI-HESI F1-extended one-generation rat reproduction protocol.
Feasibility of the ILSI-HESI (ACSA) extended one-generation protocol was tested with vinclozolin (dietary 0, 4, 20, 100mg/kg/day). Parental Wistar rats (n=25/sex/dose) were dosed pre-mating (males 4, females 2 weeks) through F1 offspring weaning (postnatal day PND21); F1 dosing continued through PND70. At PND21, 3 subsets (each 1 pup/sex/litter) were selected for neurotoxicology (functional observational battery, motor activity, neuropathology), clinical pathology (hematology, clinical chemistry, urinalysis, thyroid hormone assay) (subsets 1a, 1b; each n=10/sex/dose), immunotoxicology (IgM) SRBC antibody response and natural killer cell assays (subset 2; n=25/sex/dose), and estrus cycle (subset 3; n=25/dose). Vinclozolin reduced parental and offspring bodyweight and prostate, seminal vesicles and epididymides weight, and increased adrenal weight/induced adrenal cortical hypertrophy at 100mg/kg. Mating, fertility, gestation and lactation were unaffected. At 20 and 100mg/kg, F1 males had reduced anogenital distance and retained areolae; at 100mg/kg only, there was hypospadias, purulent prostatitis and seminal vesicle inflammation with atrophy, and Leydig cell hyperplasia, and in F1 females accelerated vaginal opening. These effects are consistent with vinclozolin's known anti-androgenic developmental effects. Neuro- and immunotoxicology tests were unaffected. F1 Only T4 was reduced at 20 and 100mg/kg. The overall sensitivity of the extended one-generation protocol is comparable to or even greater than the current two-generation study. Thus it reduces animal use while maintaining or enhancing information for risk assessment.
Schneider
Steffen
S
Department of Experimental Toxicology and Ecology, BASF SE, 67056 Ludwigshafen, Germany.
Kaufmann
Wolfgang
W
Strauss
Volker
V
van Ravenzwaay
Bennard
B
D000367:Age Factors; D000726:Androgen Antagonists / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000008:administration & dosage / Q000633:toxicity*; D005240:Feasibility Studies; D005260:Female; D005659:Fungicides, Industrial / Q000008:administration & dosage / Q000633:toxicity*; D005865:Gestational Age; D007107:Immune System / Q000187:drug effects; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D019055:No-Observed-Adverse-Effect Level; D010080:Oxazoles / Q000008:administration & dosage / Q000633:toxicity*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D012098:Reproduction / Q000187:drug effects*; D012741:Sexual Maturation / Q000187:drug effects; D013963:Thyroid Hormones / Q000097:blood; D013997:Time Factors; D018675:Toxicity Tests
D000726:Androgen Antagonists; D052244:Endocrine Disruptors; D005659:Fungicides, Industrial; D010080:Oxazoles; D013963:Thyroid Hormones; C025643:vinclozolin