Vitamin A teratogenicity and risk assessment in the macaque retinoid model

Andrew G Hendrickx, P. Peterson, D. Hartmann, H. Hummler

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Studies were performed in the cynomolgus monkey (Macaca fascicularis) to provide risk assessment information on safe dose levels of Vitamin A during human pregnancy. Vitamin A palmitate was orally administered at 7500 IU/kg (2.25 mg/kg) to 80 000 IU/kg (24 mg/kg) body weight during early pregnancy (gestation day [GD] 16-27). The results indicated a dose-related increase in exposure (AUC) to retinyl esters and retinoic acids (RA) (all-trans-RA, all- trans-4-oxo-RA, 13-cis-RA, 13-cis-4-oxo-RA). There was also a dose-related increase in abortion and malformation that affected typical retinoid target tissues in the embryo, including the craniofacial region, heart, and thymus. The NOAEL and LOAEL for structural malformations were 7500 IU/kg and 20 000 IU/kg (6 mg/kg), respectively. A companion study involving oral administration of 13-cis-RA during the same gestational period established the NOAEL for malformations at 0.5 mg/kg/day, which is close to the human therapeutic dose range (0.5 to 1.5 mg/kg/day) associated with retinoid embryopathy. Based on the known similarities in teratogenic susceptibility to 13-cis-RA, the monkey NOAEL for Vitamin A (7500 IU/kg) was used to estimate safe levels of this nutrient in humans applying a safety factor of 10. This approach yielded safe levels of Vitamin A during human pregnancy in the range of ~25 000 to 37 000 IU/day. (C) 2000 Elsevier Science Inc.

Original languageEnglish (US)
Pages (from-to)311-323
Number of pages13
JournalReproductive Toxicology
Volume14
Issue number4
DOIs
StatePublished - Jul 2000

Fingerprint

Isotretinoin
Retinoids
Macaca
Vitamin A
No-Observed-Adverse-Effect Level
Risk assessment
Pregnancy
Macaca fascicularis
Tretinoin
Thymus
Safety factor
Fetal Diseases
Nutrients
Esters
Tissue
Thymus Gland
Area Under Curve
Haplorhini
Oral Administration
Embryonic Structures

Keywords

  • 13-cis-retinoic acid
  • Accutane®
  • Kinetics
  • Long-tailed macaque
  • Retinol
  • Risk assessment
  • Teratology
  • Vitamin A

ASJC Scopus subject areas

  • Toxicology

Cite this

Vitamin A teratogenicity and risk assessment in the macaque retinoid model. / Hendrickx, Andrew G; Peterson, P.; Hartmann, D.; Hummler, H.

In: Reproductive Toxicology, Vol. 14, No. 4, 07.2000, p. 311-323.

Research output: Contribution to journalArticle

Hendrickx, Andrew G ; Peterson, P. ; Hartmann, D. ; Hummler, H. / Vitamin A teratogenicity and risk assessment in the macaque retinoid model. In: Reproductive Toxicology. 2000 ; Vol. 14, No. 4. pp. 311-323.
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abstract = "Studies were performed in the cynomolgus monkey (Macaca fascicularis) to provide risk assessment information on safe dose levels of Vitamin A during human pregnancy. Vitamin A palmitate was orally administered at 7500 IU/kg (2.25 mg/kg) to 80 000 IU/kg (24 mg/kg) body weight during early pregnancy (gestation day [GD] 16-27). The results indicated a dose-related increase in exposure (AUC) to retinyl esters and retinoic acids (RA) (all-trans-RA, all- trans-4-oxo-RA, 13-cis-RA, 13-cis-4-oxo-RA). There was also a dose-related increase in abortion and malformation that affected typical retinoid target tissues in the embryo, including the craniofacial region, heart, and thymus. The NOAEL and LOAEL for structural malformations were 7500 IU/kg and 20 000 IU/kg (6 mg/kg), respectively. A companion study involving oral administration of 13-cis-RA during the same gestational period established the NOAEL for malformations at 0.5 mg/kg/day, which is close to the human therapeutic dose range (0.5 to 1.5 mg/kg/day) associated with retinoid embryopathy. Based on the known similarities in teratogenic susceptibility to 13-cis-RA, the monkey NOAEL for Vitamin A (7500 IU/kg) was used to estimate safe levels of this nutrient in humans applying a safety factor of 10. This approach yielded safe levels of Vitamin A during human pregnancy in the range of ~25 000 to 37 000 IU/day. (C) 2000 Elsevier Science Inc.",
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