Significance of excursions of intake above the acceptable daily intake: effect of time and dose in developmental toxicology.
Three major factors to be considered in assessing the possible effects on developmental toxicology of excursions above the acceptable daily intake (ADI) are discussed. If maternal toxicity occurs at lower doses than developmental toxicity, then there may be adequate protection for the fetus if the mother is protected. In other cases, the first adverse developmental effects are usually small and reversible changes in fetal weight and it is unlikely that brief excursions, for a few days, above the ADI, would induce changes in final birth weight. The importance of excursions above the ADI on teratogenic responses would likely depend on the mechanism of teratogenesis and whether the agent acted primarily as a result of a high peak plasma level, a Cmax effect, or depended more on the total body exposure, an area under the curve (AUC) effect. This type of information is usually not available from current safety study designs. Finally, the temporal equivalence factors must be taken into account. There are 10- to 100-fold differences in time span for pre- and postnatal development up to sexual maturity, in rodents compared with humans. This can be contrasted with the relatively small pharmacokinetic differences, perhaps of up to 2- or 3-fold in plasma levels of chemicals with the same administered dose in the two species. Thus, single episodes of high chemical exposure have greater opportunity to produce permanent effects on development in rodents compared with humans. The limited evidence from acute poisonings in pregnant women tends to support this hypothesis and it seems unlikely that occasional excursions by women above the ADI would result in developmental toxic effects.
Sullivan
F M
FM
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D000014:Abnormalities, Drug-Induced; D000818:Animals; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005260:Female; D015386:Hazardous Substances / Q000493:pharmacokinetics / Q000633:toxicity*; D006801:Humans; D008452:Maximum Allowable Concentration; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D013997:Time Factors
D015386:Hazardous Substances