Physiologically-based pharmacokinetic scaling in retinoid developmental toxicity

Abstract

Requirement of the retinoids (as the retinoic acid precursors retinol and its esters) in normal embryonic development was first demonstrated in farm and laboratory animals more than 60 years ago. While there are scattered reports of anophthalmia and other terata among offspring of malnourished women [1], the requirement for adequate dietary retinol and retinyl esters in prenatal and neonatal development has been documented most clearly from intervention trials [2-4]. Bolus administration of 200 000 IU vitamin A once per month during the first four months of life in deficient populations reduced neonatal mortality 30-60% [5]. Among low birth weight infants, low hepatic and circulating retinol levels have been demonstrated [6-8]; it is evident that maternal retinoid deficiency (plasma retinoid ~10-20 μg/100 ml) increases risk of embryonic and fetal demise and precipitates retarded intrauterine growth. One factor contributing to increased mortality among neonates born to retinoid-deficient mothers is reduced development of the fetal lung [9,10]. The present U.S. National Research Council recommended daily allowance (RDA) of dietary retinoid for adults is 50001U and it is increased for pregnant/lactating women to 8000 IU (2400 retinol equivalents). The RDA values are based upon maintenance of normal dark adaptation, taking into account bioavailability and individual differences in vitamin utilization. The RDA assumes 50% of total daily intake as retinol and its esters and 50% from β-carotene.