Effect of methylmercury on midbrain cell proliferation during organogenesis: potential cross-species differences and implications for risk assessment.
5'-bromodeoxyuridine (BrdU) labeling was employed to explore the effects of methylmercury (MeHg) on cell cycle kinetics in the developing rat midbrain during gestational days (GDs) 11 to 14. Contrary to what has been previously reported in mice, no effects of MeHg on cell cycle kinetics were observed up to embryonic brain concentrations of 3-4 microg/g. The absence of an effect was confirmed using stereology and counts of midbrain cell number. Treatment with colchicine, the positive control, resulted in significant effects on cell cycle kinetics in the developing rat midbrain. The parallelogram method, borrowed from genetic toxicology, was subsequently used to place the data obtained in the present study in the context of previously collected in vitroand in vivo data on MeHg developmental neurotoxicity. This required developing a common dose metric (microg Hg/g cellular material) to allow in vitro and in vivo study comparisons. Evaluation suggested that MeHg's effects on neuronal cell proliferation show a reasonable degree of concordance across mice, rats, and humans, spanning approximately an order of magnitude. Comparisons among the in vivo data suggest that humans are at least or more sensitive than the rodent and that mice may be a slightly better model for MeHg human developmental neurotoxicity than the rat. Such comparisons can provide both a quantitative and a qualitative framework for utilizing both in vivo and in vitro data in human health risk assessment.
Lewandowski
T A
TA
Department of Environmental Health, University of Washington, Seattle, Washington 98105, USA.
Ponce
R A
RA
Charleston
J S
JS
Hong
S
S
Faustman
E M
EM
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D066298:In Vitro Techniques; D007279:Injections, Subcutaneous; D008636:Mesencephalon / Q000187:drug effects* / Q000196:embryology; D008767:Methylmercury Compounds / Q000008:administration & dosage / Q000633:toxicity*; D051379:Mice; D038081:Organogenesis / Q000187:drug effects*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D018570:Risk Assessment; D013045:Species Specificity; D013997:Time Factors
D008767:Methylmercury Compounds; C020771:methylmercury hydroxide