The role of developmental toxicity studies in acute exposure assessments: analysis of single-day vs. multiple-day exposure regimens.
In accordance with most toxicity guidelines, developmental studies typically utilize repeated exposures, usually throughout gestation or during organogenesis in particular. However, it is known that developmental toxicity may occur in response to single exposures, especially during specific windows of susceptibility. An overview of the available literature gave sufficient evidence that for many agents, the same endpoints observed in repeated dose, multiple-day studies were also observed in single-day exposures, thus indicating the relevance of developmental toxicity to health assessments of acute exposures. Further, results of benchmark dose modeling of developmental endpoints indicated that for embryo lethality, single-day exposures required a two- to fourfold higher dose than the multiple-day exposures to produce the same level of response. For fused sternebrae, exposures on specific days produced equivalent levels of response at doses that were more similar to those utilized in the repeated exposures. Appreciable differences in biological half-life (and corresponding dose metrics) as well as specific windows of susceptibility may partially explain the observed multiple- vs. single-day exposure dose-response relationships. Our results highlight the need of a more thorough evaluation of outcomes from repeated dose developmental toxicity studies in regards to their importance to chronic and acute risk assessments.
Davis
Allen
A
Oak Ridge Institute for Science and Education, Research Triangle Park, NC 27711, USA. davis.allen@epa.gov
Gift
Jeff S
JS
Woodall
George M
GM
Narotsky
Michael G
MG
Foureman
Gary L
GL
D000818:Animals; D019985:Benchmarking; D000013:Congenital Abnormalities / Q000209:etiology; D004305:Dose-Response Relationship, Drug; D020964:Embryo Loss / Q000139:chemically induced*; D047108:Embryonic Development / Q000187:drug effects; D023381:Endpoint Determination; D004785:Environmental Pollutants / Q000633:toxicity*; D005260:Female; D047109:Fetal Development / Q000187:drug effects; D005865:Gestational Age; D018811:Maternal Exposure / Q000009:adverse effects*; D008954:Models, Biological; D015233:Models, Statistical; D010795:Phthalic Acids / Q000633:toxicity; D011247:Pregnancy; D018570:Risk Assessment; D023382:Toxicity Tests, Acute / Q000379:methods* / Q000706:statistics & numerical data; D036401:Toxicity Tests, Chronic / Q000379:methods* / Q000706:statistics & numerical data; D014220:Trialkyltin Compounds / Q000633:toxicity
D004785:Environmental Pollutants; D010795:Phthalic Acids; D014220:Trialkyltin Compounds; C011559:tributyltin; C027561:butylbenzyl phthalate