Interspecies comparisons of [formula omitted] ratios: [formula omitted] ratios are not constant across species

Abstract

The hypothesis that the ratio of the adult (A) and developmental (D) toxicity of a chemical is constant across animal species has been proposed as the basis for identifying developmental hazards, both from traditional developmental toxicity screens using laboratory mammals and from alternative systems such as the coelenterate Hydra attenuata. The purpose of this study was to determine whether A D ratios are constant across species. The developmental and adult toxicity of 14 chemicals was assessed in four phylogenetically different species. The chemicals tested were aminopterin, bromodeoxyuridine, cadmium chloride, caffeine, congo red, dinocap, dinoseb, diphenylhydantoin, epinephrine, ethylenethiourea, 2-methoxyethanol, mirex, all- trans-retinoic acid, and trypan blue. These chemicals are representative of a variety of toxic mechanisms and a range of potencies. Species used were the CD-1 mouse ( Mus musculus), South African clawed frog ( Xenopus laevis), fathead minnow ( Pimephales promelas), and fruit fly ( Drosophila melanogaster). The mouse is a commonly used model for developmental toxicity. The other species are known to be sensitive to mammalian toxicants and have well-studied embryologies. Mice were exposed to chemicals either po or by sc injection using a standard Segment II protocol in which pregnant mice are administered the test agent on a daily basis from Gestation Days 6 to 15, adult toxicity is evaluated during and after treatment, and developmental toxicity is evaluated in fetuses at term. The exposure duration spans the period of organ formation in the embryo. The other species were exposed to test agents for a developmentally comparable period. This was from blastulation (shortly after fertilization) to the free-swimming tadpole stage in Xenopus (4 days); from blastulation to the free-swimming fry stage in Pimephales (7 days); and for the entire larval period, the period of development of the imaginal discs, in Drosophila (6 days). Adults of each species were exposed to test agents for 4, 7, and 6 days, respectively. The route of exposure was via the water column in the two aquatic species and via the diet in Drosophila. Statistical lowest observed effect level (LOEL) and no observed effect level (NOEL) values were generated for adult and developmental toxicity in each species. A D ratios were calculated using both LOEL and NOEL values. The results indicate little concordance of A D among species: (1) A D ratios calculated from LOEL data are within the same order of magnitude for all four species for only four chemicals: dinocap, diphenylhydantoin, epinephrine, and mirex; (2) based on NOEL data, again only four have A D ratios for all species in the same order of magnitude: dinocap, diphenylhydantion, epinephrine, and ethylenethiourea. It has been suggested that an A D ratio of 3 or greater is indicative of a developmental hazard. Using this criterion, there was consistent agreement among species only for dinocap (NOEL only), diphenylhydantoin, and all- trans-retinoic acid. Several statistical analyses for concordance were applied to the data. In no case was A D found to correlate between species. These data indicate that A D ratios are not constant across these representative species, and there is no basis for using A D for hazard assessment.