EVALUATION OF CHICK-EMBRYO NEURAL RETINA CELL-CULTURE AS A SCREEN FORDEVELOPMENTAL TOXICANTS

This paper describes a study to evaluate the concordance with in vivo results of an in vitro screen for developmental toxicants. The screen is a primary culture of chick embryo neural retina cells (CERC) which undergo processes of cell-cell recognition and interaction, growth, an d differentiation over a 7-day culture period. Each of these developme ntally significant events is measured separately as formation of multi cellular aggregates, protein content, and glutamine synthetase activit y, respectively. A total of 45 chemicals, 24 of which have been shown to be teratogenic at some dosage to mammalian embryos in utero, 7 of w hich are embryotoxic (but not teratogenic) in utero at high dosage, an d 14 of which have not produced developmental toxicity in vivo, were e valuated in this assay by investigators who were blinded to the identi ty of the chemicals. Chemicals were tested up to concentrations that w ere frankly cytolethal, or up to a maximum of 5 mg/ml. mi. Chemicals w ere present only during the first 24 hr of culture. The chemicals were selected to be representative of a variety of chemical classes (e.g., solvents, metals, food additives, anticonvulsants, antineoplastics). In several cases, pairs of structurally similar compounds with differe nt developmental toxic potencies (e.g., valproate and Zen-valproate, f ormamide, and N,N-dimethylformamide) were tested. Of the 31 developmen tal toxicants, 25 affected at least one endpoint in the assay at conce ntrations which are achievable in vivo (i.e., below the systemic conce ntration at a lethal dose), yielding a false-negative rate of 19%. Two of the nondevelopmental toxicants, saccharin, and penicillin G, had a dverse effects at concentrations below those that may be biologically achievable in vivo, giving a false-positive rate of 14%. Overall conco rdance with in vivo results by these criteria was 82%. Quantitative co mparisons were also made between the lowest observed effect concentrat ion (LOEC) in the assay and (i) lowest developmentally toxic dosage (m ostly ip) reported in rats or mice in vivo and (ii) LOEC in rodent who le embryo culture. In the first instance, 77% of the LOECs (LOELs) wer e within an order of magnitude and 93% were within a factor of 30. In the second instance 81% of the LOECs were within an order of magnitude . Potency ranking of four alkoxy acids was comparable in CERC and the in vivo rodent embryo. These results indicate that the CERC assay is c oncordant with developmental toxic potential and potency for the diver se group of compounds selected, and that it could serve as a prelimina ry screen for developmental toxicity. (C) 1995 Society of Toxicology.