The road to embryologically based dose-response models.
The goal of researchers working in the area of developmental toxicology is to prevent adverse reproductive outcomes (early pregnancy loss, birth defects, reduced birth weight, and altered functional development) in humans due to exposures to environmental contaminants, therapeutic drugs, and other factors. To best achieve that goal, it is important that relevant information be gathered and assimilated in the risk assessment process. One of the major challenges of improved risk assessment is to better use all pertinent biological and mechanistic information. This may be done qualitatively (e.g., demonstrating that the experimental model is not appropriate for extrapolation purposes); semiquantitatively (using information to reduce the degree of uncertainty present under default extrapolation procedures), or quantitatively (formally describing the relationships between exposure and adverse outcome in mathematical forms, including components that directly reflect individual steps in the overall progression of toxicity). In this paper we review the recent advances in the risk assessment process for developmental toxicants and hypothesize on future directions that may revolutionize our thinking in this area. The road to these changes sometimes appears to be a well-mapped course on a relatively smooth surface; at other times the path is bumpy and obscure, while at still other times it is only a wish in the eye of the engineer to cross an uncharted and rugged environment.
Kavlock
R J
RJ
National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. kavlock@herl45.herl.epa.gov
Setzer
R W
RW
D000014:Abnormalities, Drug-Induced / Q000209:etiology*; D000818:Animals; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000187:drug effects* / Q000648:ultrastructure; D004781:Environmental Exposure; D005472:Fluorouracil / Q000633:toxicity; D005801:Genes, Homeobox; D006801:Humans; D008954:Models, Biological; D018570:Risk Assessment; D013723:Teratogens / Q000633:toxicity*
D013723:Teratogens; D005472:Fluorouracil