Skip to main content
PMC home page
Environmental Health Perspectives logoLink to Environmental Health Perspectives
. 2004 Feb;112(2):272–283. doi: 10.1289/ehp.6013

Incorporating children's toxicokinetics into a risk framework.

Gary Ginsberg 1, William Slikker Jr 1, James Bruckner 1, Babasaheb Sonawane 1
PMCID: PMC1241838  PMID: 14754583

Abstract

Children's responses to environmental toxicants will be affected by the way in which their systems absorb, distribute, metabolize, and excrete chemicals. These toxicokinetic factors vary during development, from in utero where maternal and placental processes play a large role, to the neonate in which emerging metabolism and clearance pathways are key determinants. Toxicokinetic differences between neonates and adults lead to the potential for internal dosimetry differences and increased or decreased risk, depending on the mechanisms for toxicity and clearance of a given chemical. This article raises a number of questions that need to be addressed when conducting a toxicokinetic analysis of in utero or childhood exposures. These questions are organized into a proposed framework for conducting the assessment that involves problem formulation (identification of early life stage toxicokinetic factors and chemical-specific factors that may raise questions/concerns for children); data analysis (development of analytic approach, construction of child/adult or child/animal dosimetry comparisons); and risk characterization (evaluation of how children's toxicokinetic analysis can be used to decrease uncertainties in the risk assessment). The proposed approach provides a range of analytical options, from qualitative to quantitative, for assessing children's dosimetry. Further, it provides background information on a variety of toxicokinetic factors that can vary as a function of developmental stage. For example, the ontology of metabolizing systems is described via reference to pediatric studies involving therapeutic drugs and evidence from in vitro enzyme studies. This type of resource information is intended to help the assessor begin to address the issues raised in this paper.

Full Text

The Full Text of this article is available as a PDF (196.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. AUGUSTINSSON K. B., BARR M. AGE VARIATION IN PLASMA ARYLESTERASE ACTIVITY IN CHILDREN. Clin Chim Acta. 1963 Jul;8:568–573. doi: 10.1016/0009-8981(63)90106-2. [DOI] [PubMed] [Google Scholar]
  2. Adinolfi M. The development of the human blood-CSF-brain barrier. Dev Med Child Neurol. 1985 Aug;27(4):532–537. doi: 10.1111/j.1469-8749.1985.tb04581.x. [DOI] [PubMed] [Google Scholar]
  3. Andersen M. E., Clewell H. J., 3rd, Gargas M. L., Smith F. A., Reitz R. H. Physiologically based pharmacokinetics and the risk assessment process for methylene chloride. Toxicol Appl Pharmacol. 1987 Feb;87(2):185–205. doi: 10.1016/0041-008x(87)90281-x. [DOI] [PubMed] [Google Scholar]
  4. Andersen M. E., Clewell H., 3rd, Krishnan K. Tissue dosimetry, pharmacokinetic modeling, and interspecies scaling factors. Risk Anal. 1995 Aug;15(4):533–537. doi: 10.1111/j.1539-6924.1995.tb00346.x. [DOI] [PubMed] [Google Scholar]
  5. Anderson B. J., McKee A. D., Holford N. H. Size, myths and the clinical pharmacokinetics of analgesia in paediatric patients. Clin Pharmacokinet. 1997 Nov;33(5):313–327. doi: 10.2165/00003088-199733050-00001. [DOI] [PubMed] [Google Scholar]
  6. Arcuri F., Sestini S., Cintorino M. Expression of 11 beta-hydroxysteroid dehydrogenase in early pregnancy: implications in human trophoblast-endometrial interactions. Semin Reprod Endocrinol. 1999;17(1):53–61. doi: 10.1055/s-2007-1016212. [DOI] [PubMed] [Google Scholar]
  7. Atterberry T. T., Burnett W. T., Chambers J. E. Age-related differences in parathion and chlorpyrifos toxicity in male rats: target and nontarget esterase sensitivity and cytochrome P450-mediated metabolism. Toxicol Appl Pharmacol. 1997 Dec;147(2):411–418. doi: 10.1006/taap.1997.8303. [DOI] [PubMed] [Google Scholar]
  8. Behrman R. E., Lees M. H., Peterson E. N., De Lannoy C. W., Seeds A. E. Distribution of the circulation in the normal and asphyxiated fetal primate. Am J Obstet Gynecol. 1970 Nov 15;108(6):956–969. doi: 10.1016/0002-9378(70)90341-8. [DOI] [PubMed] [Google Scholar]
  9. Benke G. M., Murphy S. D. The influence of age on the toxicity and metabolism of methyl parathion and parathion in male and female rats. Toxicol Appl Pharmacol. 1975 Feb;31(2):254–269. doi: 10.1016/0041-008x(75)90161-1. [DOI] [PubMed] [Google Scholar]
  10. Bertz R. J., Granneman G. R. Use of in vitro and in vivo data to estimate the likelihood of metabolic pharmacokinetic interactions. Clin Pharmacokinet. 1997 Mar;32(3):210–258. doi: 10.2165/00003088-199732030-00004. [DOI] [PubMed] [Google Scholar]
  11. Besunder J. B., Reed M. D., Blumer J. L. Principles of drug biodisposition in the neonate. A critical evaluation of the pharmacokinetic-pharmacodynamic interface (Part I). Clin Pharmacokinet. 1988 Apr;14(4):189–216. doi: 10.2165/00003088-198814040-00001. [DOI] [PubMed] [Google Scholar]
  12. Bogaert M. C., Thiery M. Pharmacokinetics and pregnancy. Eur J Obstet Gynecol Reprod Biol. 1983 Dec;16(4):229–235. doi: 10.1016/0028-2243(83)90139-9. [DOI] [PubMed] [Google Scholar]
  13. Bois F. Y., Zeise L., Tozer T. N. Precision and sensitivity of pharmacokinetic models for cancer risk assessment: tetrachloroethylene in mice, rats, and humans. Toxicol Appl Pharmacol. 1990 Feb;102(2):300–315. doi: 10.1016/0041-008x(90)90029-t. [DOI] [PubMed] [Google Scholar]
  14. Brock-Utne J. G., Downing J. W., Mankowitz E. Drugs and the fetomaternal unit. S Afr Med J. 1980 Aug 30;58(9):366–369. [PubMed] [Google Scholar]
  15. Bruckner J. V. Differences in sensitivity of children and adults to chemical toxicity: the NAS panel report. Regul Toxicol Pharmacol. 2000 Jun;31(3):280–285. doi: 10.1006/rtph.2000.1393. [DOI] [PubMed] [Google Scholar]
  16. Carpenter S. P., Savage D. D., Schultz E. D., Raucy J. L. Ethanol-mediated transplacental induction of CYP2E1 in fetal rat liver. J Pharmacol Exp Ther. 1997 Aug;282(2):1028–1036. [PubMed] [Google Scholar]
  17. Cazeneuve C., Pons G., Rey E., Treluyer J. M., Cresteil T., Thiroux G., D'Athis P., Olive G. Biotransformation of caffeine in human liver microsomes from foetuses, neonates, infants and adults. Br J Clin Pharmacol. 1994 May;37(5):405–412. doi: 10.1111/j.1365-2125.1994.tb05706.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Chen H., Brzezinski M. R., Fantel A. G., Juchau M. R. Catalysis of drug oxidation during embryogenesis in human hepatic tissues using imipramine as a model substrate. Drug Metab Dispos. 1999 Nov;27(11):1306–1308. [PubMed] [Google Scholar]
  19. Cummings A. J. A survey of pharmacokinetic data from pregnant women. Clin Pharmacokinet. 1983 Jul-Aug;8(4):344–354. doi: 10.2165/00003088-198308040-00005. [DOI] [PubMed] [Google Scholar]
  20. DANCIS J., MONEY W. L., CONDON G. P., LEVITZ M. The relative transfer of estrogens and their glucuronides across the placenta in the guinea pig. J Clin Invest. 1958 Oct;37(10):1373–1378. doi: 10.1172/JCI103727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. DONE A. K. DEVELOPMENTAL PHARMACOLOGY. Clin Pharmacol Ther. 1964 Jul-Aug;5:432–479. doi: 10.1002/cpt196454432. [DOI] [PubMed] [Google Scholar]
  22. Daston George, Faustman Elaine, Ginsberg Gary, Fenner-Crisp Penny, Olin Stephen, Sonawane Babasaheb, Bruckner James, Breslin William, McLaughlin Tara J. A framework for assessing risks to children from exposure to environmental agents. Environ Health Perspect. 2004 Feb;112(2):238–256. doi: 10.1289/ehp.6182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Davis J. M., Otto D. A., Weil D. E., Grant L. D. The comparative developmental neurotoxicity of lead in humans and animals. Neurotoxicol Teratol. 1990 May-Jun;12(3):215–229. doi: 10.1016/0892-0362(90)90093-r. [DOI] [PubMed] [Google Scholar]
  24. Dempsey D., Jacob P., 3rd, Benowitz N. L. Nicotine metabolism and elimination kinetics in newborns. Clin Pharmacol Ther. 2000 May;67(5):458–465. doi: 10.1067/mcp.2000.106129. [DOI] [PubMed] [Google Scholar]
  25. Diggory H. J., Landrigan P. J., Latimer K. P., Ellington A. C., Kimbrough R. D., Liddle J. A., Cline R. E., Smrek A. L. Fatal parathion poisoning caused by contamination of flour in international commerce. Am J Epidemiol. 1977 Aug;106(2):145–153. doi: 10.1093/oxfordjournals.aje.a112444. [DOI] [PubMed] [Google Scholar]
  26. Dorne J. L., Walton K., Renwick A. G. Uncertainty factors for chemical risk assessment. human variability in the pharmacokinetics of CYP1A2 probe substrates. Food Chem Toxicol. 2001 Jul;39(7):681–696. doi: 10.1016/s0278-6915(01)00005-9. [DOI] [PubMed] [Google Scholar]
  27. Dutton G. J. Developmental aspects of drug conjugation, with special reference to glucuronidation. Annu Rev Pharmacol Toxicol. 1978;18:17–35. doi: 10.1146/annurev.pa.18.040178.000313. [DOI] [PubMed] [Google Scholar]
  28. Dutton G. J., Leakey J. E. The perinatal development of drug-metabolizing enzymes: what factors trigger their onset? Prog Drug Res. 1981;25:189–273. [PubMed] [Google Scholar]
  29. Dziegielewska K. M., Knott G. W., Saunders N. R. The nature and composition of the internal environment of the developing brain. Cell Mol Neurobiol. 2000 Feb;20(1):41–56. doi: 10.1023/a:1006943926765. [DOI] [PubMed] [Google Scholar]
  30. Ecobichon D. J., Stephens D. S. Perinatal development of human blood esterases. Clin Pharmacol Ther. 1973 Jan-Feb;14(1):41–47. doi: 10.1002/cpt197314141. [DOI] [PubMed] [Google Scholar]
  31. Eichelbaum M., Ekbom K., Bertilsson L., Ringberger V. A., Rane A. Plasma kinetics of carbamazepine and its epoxide metabolite in man after single and multiple doses. Eur J Clin Pharmacol. 1975 Jun 13;8(5):337–341. doi: 10.1007/BF00562659. [DOI] [PubMed] [Google Scholar]
  32. Eichelbaum M., Tomson T., Tybring G., Bertilsson L. Carbamazepine metabolism in man. Induction and pharmacogenetic aspects. Clin Pharmacokinet. 1985 Jan-Feb;10(1):80–90. doi: 10.2165/00003088-198510010-00004. [DOI] [PubMed] [Google Scholar]
  33. Eltom S. E., Babish J. G., Schwark W. S. The postnatal development of drug-metabolizing enzymes in hepatic, pulmonary and renal tissues of the goat. J Vet Pharmacol Ther. 1993 Jun;16(2):152–163. doi: 10.1111/j.1365-2885.1993.tb00159.x. [DOI] [PubMed] [Google Scholar]
  34. Farin F. M., Omiecinski C. J. Regiospecific expression of cytochrome P-450s and microsomal epoxide hydrolase in human brain tissue. J Toxicol Environ Health. 1993 Oct-Nov;40(2-3):317–335. doi: 10.1080/15287399309531797. [DOI] [PubMed] [Google Scholar]
  35. Gibbs J. P., Murray G., Risler L., Chien J. Y., Dev R., Slattery J. T. Age-dependent tetrahydrothiophenium ion formation in young children and adults receiving high-dose busulfan. Cancer Res. 1997 Dec 15;57(24):5509–5516. [PubMed] [Google Scholar]
  36. Ginsberg Gary, Hattis Dale, Sonawane Babasaheb, Russ Abel, Banati Prerna, Kozlak Mary, Smolenski Susan, Goble Rob. Evaluation of child/adult pharmacokinetic differences from a database derived from the therapeutic drug literature. Toxicol Sci. 2002 Apr;66(2):185–200. doi: 10.1093/toxsci/66.2.185. [DOI] [PubMed] [Google Scholar]
  37. Goebelsmann U., Roberts J. M., Jaffe R. B. Placental transfer of 3 H-oestriol-3-sulphate-16-glucosiduronate and 3 H-oestriol-16-glucosiduronate- 14 C. Acta Endocrinol (Copenh) 1972 May;70(1):132–142. doi: 10.1530/acta.0.0700132. [DOI] [PubMed] [Google Scholar]
  38. Goebelsmann U., Wiqvist N., Diczfalusy E. Placental transfer of oestriol glucosiduronates. Acta Endocrinol (Copenh) 1968 Nov;59(3):426–432. doi: 10.1530/acta.0.0590426. [DOI] [PubMed] [Google Scholar]
  39. Goldenthal E. I. A compilation of LD50 values in newborn and adult animals. Toxicol Appl Pharmacol. 1971 Jan;18(1):185–207. doi: 10.1016/0041-008x(71)90328-0. [DOI] [PubMed] [Google Scholar]
  40. Greiss F. C., Jr, Gobble F. L., Jr Effect of sympathetic nerve stimulation on the uterine vascular bed. Am J Obstet Gynecol. 1967 Apr 1;97(7):962–967. doi: 10.1016/0002-9378(67)90524-8. [DOI] [PubMed] [Google Scholar]
  41. Hakkola J., Pasanen M., Pelkonen O., Hukkanen J., Evisalmi S., Anttila S., Rane A., Mäntylä M., Purkunen R., Saarikoski S. Expression of CYP1B1 in human adult and fetal tissues and differential inducibility of CYP1B1 and CYP1A1 by Ah receptor ligands in human placenta and cultured cells. Carcinogenesis. 1997 Feb;18(2):391–397. doi: 10.1093/carcin/18.2.391. [DOI] [PubMed] [Google Scholar]
  42. Hakkola J., Pasanen M., Purkunen R., Saarikoski S., Pelkonen O., Mäenpä J., Rane A., Raunio H. Expression of xenobiotic-metabolizing cytochrome P450 forms in human adult and fetal liver. Biochem Pharmacol. 1994 Jul 5;48(1):59–64. doi: 10.1016/0006-2952(94)90223-2. [DOI] [PubMed] [Google Scholar]
  43. Hakkola J., Pelkonen O., Pasanen M., Raunio H. Xenobiotic-metabolizing cytochrome P450 enzymes in the human feto-placental unit: role in intrauterine toxicity. Crit Rev Toxicol. 1998 Jan;28(1):35–72. doi: 10.1080/10408449891344173. [DOI] [PubMed] [Google Scholar]
  44. Hakkola J., Tanaka E., Pelkonen O. Developmental expression of cytochrome P450 enzymes in human liver. Pharmacol Toxicol. 1998 May;82(5):209–217. doi: 10.1111/j.1600-0773.1998.tb01427.x. [DOI] [PubMed] [Google Scholar]
  45. Harroff H. H., Jr Use of animal models in pediatric research. Adv Pediatr. 1997;44:453–489. [PubMed] [Google Scholar]
  46. Hattis D., White P., Koch P. Uncertainties in pharmacokinetic modeling for perchloroethylene: II. Comparison of model predictions with data for a variety of different parameters. Risk Anal. 1993 Dec;13(6):599–610. doi: 10.1111/j.1539-6924.1993.tb01322.x. [DOI] [PubMed] [Google Scholar]
  47. Idänpän-Heikkilä J., Jouppila P., Akerblom H. K., Isoaho R., Kauppila E., Koivisto M. Elimination and metabolic effects of ethanol in mother, fetus, and newborn infant. Am J Obstet Gynecol. 1972 Feb 1;112(3):387–393. doi: 10.1016/0002-9378(72)90483-8. [DOI] [PubMed] [Google Scholar]
  48. Illsley N. P., Hall S., Penfold P., Stacey T. E. Diffusional permeability of the human placenta. Contrib Gynecol Obstet. 1985;13:92–97. [PubMed] [Google Scholar]
  49. Imaoka S., Fujita S., Funae Y. Age-dependent expression of cytochrome P-450s in rat liver. Biochim Biophys Acta. 1991 Oct 21;1097(3):187–192. doi: 10.1016/0925-4439(91)90034-7. [DOI] [PubMed] [Google Scholar]
  50. Jahn F., Reuter A., Karge E., Danz M., Klinger W. Age dependent different influence of carbon tetrachloride on biotransformation of xenobiotics, glutathione content, lipid peroxidation and histopathology of rat liver. Exp Toxicol Pathol. 1993 May;45(2-3):101–107. doi: 10.1016/S0940-2993(11)80477-X. [DOI] [PubMed] [Google Scholar]
  51. Juchau M. R., Faustman-Watts E. Pharmacokinetic considerations in the maternal-placental-fetal unit. Clin Obstet Gynecol. 1983 Jun;26(2):379–390. doi: 10.1097/00003081-198306000-00020. [DOI] [PubMed] [Google Scholar]
  52. Jusko W. J. Pharmacokinetic principles in pediatric pharmacology. Pediatr Clin North Am. 1972 Feb;19(1):81–100. doi: 10.1016/s0031-3955(16)32668-2. [DOI] [PubMed] [Google Scholar]
  53. Kim C. S., Binienda Z., Sandberg J. A. Construction of a physiologically based pharmacokinetic model for 2,4-dichlorophenoxyacetic acid dosimetry in the developing rabbit brain. Toxicol Appl Pharmacol. 1996 Feb;136(2):250–259. doi: 10.1006/taap.1996.0032. [DOI] [PubMed] [Google Scholar]
  54. Kivalo I., Saarikoski S. Placental transmission and foetal uptake of 14 C-dimethyltubocurarine. Br J Anaesth. 1972 Jun;44(6):557–561. doi: 10.1093/bja/44.6.557. [DOI] [PubMed] [Google Scholar]
  55. Korinthenberg R., Haug C., Hannak D. The metabolization of carbamazepine to CBZ-10,11-epoxide in children from the newborn age to adolescence. Neuropediatrics. 1994 Aug;25(4):214–216. doi: 10.1055/s-2008-1073024. [DOI] [PubMed] [Google Scholar]
  56. Kostial K., Kello D., Jugo S., Rabar I., Maljković T. Influence of age on metal metabolism and toxicity. Environ Health Perspect. 1978 Aug;25:81–86. doi: 10.1289/ehp.782581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Krauer B., Krauer F., Hytten F. E. Drug disposition and pharmacokinetics in the maternal-placental-fetal unit. Pharmacol Ther. 1980;10(2):301–328. doi: 10.1016/0163-7258(80)90085-6. [DOI] [PubMed] [Google Scholar]
  58. Kurata N., Nishimura Y., Iwase M., Fischer N. E., Tang B. K., Inaba T., Yasuhara H. Trimethadione metabolism by human liver cytochrome P450: evidence for the involvement of CYP2E1. Xenobiotica. 1998 Nov;28(11):1041–1047. doi: 10.1080/004982598238930. [DOI] [PubMed] [Google Scholar]
  59. LEHMANN H., COOK J., RYAN E. Pseudocholinesterase in early infancy. Proc R Soc Med. 1957 Mar;50(3):147–150. [PMC free article] [PubMed] [Google Scholar]
  60. LEVITZ M., CONDON G. P., MONEY W. L., DANCIS J. The relative transfer of estrogens and their sulfates across the guinea pig placenta: sulfurylation of estrogens by the placenta. J Biol Chem. 1960 Apr;235:973–977. [PubMed] [Google Scholar]
  61. Lacroix D., Sonnier M., Moncion A., Cheron G., Cresteil T. Expression of CYP3A in the human liver--evidence that the shift between CYP3A7 and CYP3A4 occurs immediately after birth. Eur J Biochem. 1997 Jul 15;247(2):625–634. doi: 10.1111/j.1432-1033.1997.00625.x. [DOI] [PubMed] [Google Scholar]
  62. Levy G., Khanna N. N., Soda D. M., Tsuzuki O., Stern L. Pharmacokinetics of acetaminophen in the human neonate: formation of acetaminophen glucuronide and sulfate in relation to plasma bilirubin concentration and D-glucaric acid excretion. Pediatrics. 1975 Jun;55(6):818–825. [PubMed] [Google Scholar]
  63. Lin J. H. Species similarities and differences in pharmacokinetics. Drug Metab Dispos. 1995 Oct;23(10):1008–1021. [PubMed] [Google Scholar]
  64. Luecke R. H., Wosilait W. D., Pearce B. A., Young J. F. A physiologically based pharmacokinetic computer model for human pregnancy. Teratology. 1994 Feb;49(2):90–103. doi: 10.1002/tera.1420490205. [DOI] [PubMed] [Google Scholar]
  65. Mattsson J. L., Maurissen J. P., Nolan R. J., Brzak K. A. Lack of differential sensitivity to cholinesterase inhibition in fetuses and neonates compared to dams treated perinatally with chlorpyrifos. Toxicol Sci. 2000 Feb;53(2):438–446. doi: 10.1093/toxsci/53.2.438. [DOI] [PubMed] [Google Scholar]
  66. Mihaly G. W., Morgan D. J. Placental drug transfer: effects of gestational age and species. Pharmacol Ther. 1983;23(2):253–266. doi: 10.1016/0163-7258(83)90015-3. [DOI] [PubMed] [Google Scholar]
  67. Millicovsky G., DeSesso J. M. Differential embryonic cardiovascular responses to acute maternal uterine ischemia: an in vivo microscopic study of rabbit embryos with either intact or clamped umbilical cords. Teratology. 1980 Dec;22(3):335–343. doi: 10.1002/tera.1420220311. [DOI] [PubMed] [Google Scholar]
  68. Moghrabi N., Head J. R., Andersson S. Cell type-specific expression of 17 beta-hydroxysteroid dehydrogenase type 2 in human placenta and fetal liver. J Clin Endocrinol Metab. 1997 Nov;82(11):3872–3878. doi: 10.1210/jcem.82.11.4391. [DOI] [PubMed] [Google Scholar]
  69. Morata Thais C. Interaction between noise and asphyxiants: a concern for toxicology and occupational health. Toxicol Sci. 2002 Mar;66(1):1–3. doi: 10.1093/toxsci/66.1.1. [DOI] [PubMed] [Google Scholar]
  70. Morselli P. L. Clinical pharmacology of the perinatal period and early infancy. Clin Pharmacokinet. 1989;17 (Suppl 1):13–28. doi: 10.2165/00003088-198900171-00004. [DOI] [PubMed] [Google Scholar]
  71. Moser V. C., Chanda S. M., Mortensen S. R., Padilla S. Age- and gender-related differences in sensitivity to chlorpyrifos in the rat reflect developmental profiles of esterase activities. Toxicol Sci. 1998 Dec;46(2):211–222. doi: 10.1006/toxs.1998.2526. [DOI] [PubMed] [Google Scholar]
  72. Mulhall A., de Louvois J., Hurley R. Chloramphenicol toxicity in neonates: its incidence and prevention. Br Med J (Clin Res Ed) 1983 Nov 12;287(6403):1424–1427. doi: 10.1136/bmj.287.6403.1424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Murray G. I., Foster C. O., Barnes T. S., Weaver R. J., Snyder C. P., Ewen S. W., Melvin W. T., Burke M. D. Cytochrome P450IA expression in adult and fetal human liver. Carcinogenesis. 1992 Feb;13(2):165–169. doi: 10.1093/carcin/13.2.165. [DOI] [PubMed] [Google Scholar]
  74. Mäenpä J., Rane A., Raunio H., Honkakoski P., Pelkonen O. Cytochrome P450 isoforms in human fetal tissues related to phenobarbital-inducible forms in the mouse. Biochem Pharmacol. 1993 Feb 24;45(4):899–907. doi: 10.1016/0006-2952(93)90175-v. [DOI] [PubMed] [Google Scholar]
  75. Nedelcheva V., Gut I. P450 in the rat and man: methods of investigation, substrate specificities and relevance to cancer. Xenobiotica. 1994 Dec;24(12):1151–1175. doi: 10.3109/00498259409038673. [DOI] [PubMed] [Google Scholar]
  76. Neims A. H., Warner M., Loughnan P. M., Aranda J. V. Developmental aspects of the hepatic cytochrome P450 monooxygenase system. Annu Rev Pharmacol Toxicol. 1976;16:427–445. doi: 10.1146/annurev.pa.16.040176.002235. [DOI] [PubMed] [Google Scholar]
  77. O'Flaherty E. J. Physiologically based models for bone-seeking elements. II. Kinetics of lead disposition in rats. Toxicol Appl Pharmacol. 1991 Nov;111(2):313–331. doi: 10.1016/0041-008x(91)90033-b. [DOI] [PubMed] [Google Scholar]
  78. Ohmori S., Nakasa H., Asanome K., Kurose Y., Ishii I., Hosokawa M., Kitada M. Differential catalytic properties in metabolism of endogenous and exogenous substrates among CYP3A enzymes expressed in COS-7 cells. Biochim Biophys Acta. 1998 May 8;1380(3):297–304. doi: 10.1016/s0304-4165(97)00156-6. [DOI] [PubMed] [Google Scholar]
  79. Pariente-Khayat A., Pons G., Rey E., Richard M. O., D'Athis P., Moran C., Badoual J., Olive G. Caffeine acetylator phenotyping during maturation in infants. Pediatr Res. 1991 May;29(5):492–495. doi: 10.1203/00006450-199105010-00015. [DOI] [PubMed] [Google Scholar]
  80. Parsons W. D., Neims A. H. Effect of smoking on caffeine clearance. Clin Pharmacol Ther. 1978 Jul;24(1):40–45. doi: 10.1002/cpt197824140. [DOI] [PubMed] [Google Scholar]
  81. Pelekis M., Gephart L. A., Lerman S. E. Physiological-model-based derivation of the adult and child pharmacokinetic intraspecies uncertainty factors for volatile organic compounds. Regul Toxicol Pharmacol. 2001 Feb;33(1):12–20. doi: 10.1006/rtph.2000.1436. [DOI] [PubMed] [Google Scholar]
  82. Pikkarainen P. H., Räihä N. C. Development of alcohol dehydrogenase activity in the human liver. Pediatr Res. 1967 May;1(3):165–168. doi: 10.1203/00006450-196705000-00001. [DOI] [PubMed] [Google Scholar]
  83. Pons G., Rey E., Carrier O., Richard M. O., Moran C., Badoual J., Olive G. Maturation of AFMU excretion in infants. Fundam Clin Pharmacol. 1989;3(6):589–595. doi: 10.1111/j.1472-8206.1989.tb00461.x. [DOI] [PubMed] [Google Scholar]
  84. Pounds J. G., Marlar R. J., Allen J. R. Metabolism of lead-210 in juvenile and adult rhesus monkeys (Macaca mulatta). Bull Environ Contam Toxicol. 1978 Jun;19(6):684–691. doi: 10.1007/BF01685858. [DOI] [PubMed] [Google Scholar]
  85. Power G. G., Longo L. D. Fetal circulation times and their implications for tissue oxygenation. Gynecol Invest. 1975;6(6):342–355. doi: 10.1159/000301534. [DOI] [PubMed] [Google Scholar]
  86. Pynnönen S., Sillanpä M., Frey H., Iisalo E. Carbamazepine and its 10,11-epoxide in children and adults with epilepsy. Eur J Clin Pharmacol. 1977 Jan 3;11(2):129–133. doi: 10.1007/BF00562904. [DOI] [PubMed] [Google Scholar]
  87. Rane A., Tomson G. Prenatal and neonatal drug metabolism in man. Eur J Clin Pharmacol. 1980 Jul;18(1):9–15. doi: 10.1007/BF00561473. [DOI] [PubMed] [Google Scholar]
  88. Rao H. V., Ginsberg G. L. A physiologically-based pharmacokinetic model assessment of methyl t-butyl ether in groundwater for a bathing and showering determination. Risk Anal. 1997 Oct;17(5):583–598. doi: 10.1111/j.1539-6924.1997.tb00899.x. [DOI] [PubMed] [Google Scholar]
  89. Rasheed A., Hines R. N., McCarver-May D. G. Variation in induction of human placental CYP2E1: possible role in susceptibility to fetal alcohol syndrome? Toxicol Appl Pharmacol. 1997 Jun;144(2):396–400. doi: 10.1006/taap.1997.8152. [DOI] [PubMed] [Google Scholar]
  90. Ratanasavanh D., Beaune P., Morel F., Flinois J. P., Guengerich F. P., Guillouzo A. Intralobular distribution and quantitation of cytochrome P-450 enzymes in human liver as a function of age. Hepatology. 1991 Jun;13(6):1142–1151. [PubMed] [Google Scholar]
  91. Ravindranath V., Boyd M. R. Xenobiotic metabolism in brain. Drug Metab Rev. 1995;27(3):419–448. doi: 10.3109/03602539508998330. [DOI] [PubMed] [Google Scholar]
  92. Renwick A. G., Dorne J. L., Walton K. An analysis of the need for an additional uncertainty factor for infants and children. Regul Toxicol Pharmacol. 2000 Jun;31(3):286–296. doi: 10.1006/rtph.2000.1394. [DOI] [PubMed] [Google Scholar]
  93. Rudolph A. M., Heymann M. A. The circulation of the fetus in utero. Methods for studying distribution of blood flow, cardiac output and organ blood flow. Circ Res. 1967 Aug;21(2):163–184. doi: 10.1161/01.res.21.2.163. [DOI] [PubMed] [Google Scholar]
  94. Sandberg J. A., Binienda Z., Lipe G., Rose L. M., Parker W. B., Ali S. F., Slikker W., Jr Placental transfer and fetal disposition of 2',3'-dideoxycytidine and 2',3'-dideoxyinosine in the rhesus monkey. Drug Metab Dispos. 1995 Aug;23(8):881–884. [PubMed] [Google Scholar]
  95. Slikker W., Jr, Hill D. E., Young J. F. Comparison of the transplacental pharmacokinetics of 17 beta-estradiol and diethylstilbestrol in the subhuman primate. J Pharmacol Exp Ther. 1982 Apr;221(1):173–182. [PubMed] [Google Scholar]
  96. Slikker W., Jr The role of metabolism in the testing of developmental toxicants. Regul Toxicol Pharmacol. 1987 Dec;7(4):390–413. doi: 10.1016/0273-2300(87)90060-2. [DOI] [PubMed] [Google Scholar]
  97. Sonnier M., Cresteil T. Delayed ontogenesis of CYP1A2 in the human liver. Eur J Biochem. 1998 Feb 1;251(3):893–898. doi: 10.1046/j.1432-1327.1998.2510893.x. [DOI] [PubMed] [Google Scholar]
  98. Stevens J. C., Shipley L. A., Cashman J. R., Vandenbranden M., Wrighton S. A. Comparison of human and rhesus monkey in vitro phase I and phase II hepatic drug metabolism activities. Drug Metab Dispos. 1993 Sep-Oct;21(5):753–760. [PubMed] [Google Scholar]
  99. Strange R. C., Howie A. F., Hume R., Matharoo B., Bell J., Hiley C., Jones P., Beckett G. J. The development expression of alpha-, mu- and pi-class glutathione S-transferases in human liver. Biochim Biophys Acta. 1989 Dec 8;993(2-3):186–190. doi: 10.1016/0304-4165(89)90162-1. [DOI] [PubMed] [Google Scholar]
  100. Szórády I., Sánta A., Veress I. Drug acetylator phenotypes in newborn infants. Biol Res Pregnancy Perinatol. 1987;8(1 1ST):23–25. [PubMed] [Google Scholar]
  101. Tanaka E. In vivo age-related changes in hepatic drug-oxidizing capacity in humans. J Clin Pharm Ther. 1998 Aug;23(4):247–255. doi: 10.1046/j.1365-2710.1998.00164.x. [DOI] [PubMed] [Google Scholar]
  102. Treluyer J. M., Cheron G., Sonnier M., Cresteil T. Cytochrome P-450 expression in sudden infant death syndrome. Biochem Pharmacol. 1996 Aug 9;52(3):497–504. doi: 10.1016/0006-2952(96)00253-5. [DOI] [PubMed] [Google Scholar]
  103. Treluyer J. M., Jacqz-Aigrain E., Alvarez F., Cresteil T. Expression of CYP2D6 in developing human liver. Eur J Biochem. 1991 Dec 5;202(2):583–588. doi: 10.1111/j.1432-1033.1991.tb16411.x. [DOI] [PubMed] [Google Scholar]
  104. Vest M. F. The development of conjugation mechanisms and drug toxicity in the newborn. Biol Neonat. 1965;8(5):258–266. doi: 10.1159/000239961. [DOI] [PubMed] [Google Scholar]
  105. Vieira I., Sonnier M., Cresteil T. Developmental expression of CYP2E1 in the human liver. Hypermethylation control of gene expression during the neonatal period. Eur J Biochem. 1996 Jun 1;238(2):476–483. doi: 10.1111/j.1432-1033.1996.0476z.x. [DOI] [PubMed] [Google Scholar]
  106. Waddell W. J., Marlowe C. Transfer of drugs across the placenta. Pharmacol Ther. 1981;14(3):375–390. doi: 10.1016/0163-7258(81)90034-6. [DOI] [PubMed] [Google Scholar]
  107. Watanabe J., Asaka Y., Kanamura S. Postnatal development and sublobular distribution of cytochrome P-450 in rat liver: a microphotometric study. J Histochem Cytochem. 1993 Mar;41(3):397–400. doi: 10.1177/41.3.8429202. [DOI] [PubMed] [Google Scholar]
  108. Welfare M. R., Bassendine M. F., Daly A. K. The effect of NAT2 genotype and gender on the metabolism of caffeine in nonsmoking subjects. Br J Clin Pharmacol. 2000 Mar;49(3):240–243. doi: 10.1046/j.1365-2125.2000.00130.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  109. Welsch F., Blumenthal G. M., Conolly R. B. Physiologically based pharmacokinetic models applicable to organogenesis: extrapolation between species and potential use in prenatal toxicity risk assessments. Toxicol Lett. 1995 Dec;82-83:539–547. doi: 10.1016/0378-4274(95)03499-4. [DOI] [PubMed] [Google Scholar]
  110. Welsch F. Placental transfer and fetal uptake of drugs. J Vet Pharmacol Ther. 1982 Jun;5(2):91–104. doi: 10.1111/j.1365-2885.1982.tb00504.x. [DOI] [PubMed] [Google Scholar]
  111. Wilson J. G., Ritter E. J., Scott W. J., Fradkin R. Comparative distribution and embryotoxicity of acetylsalicylic acid in pregnant rats and rhesus monkeys. Toxicol Appl Pharmacol. 1977 Jul;41(1):67–78. doi: 10.1016/0041-008x(77)90054-0. [DOI] [PubMed] [Google Scholar]
  112. Yang H. Y., Namkung M. J., Juchau M. R. Expression of functional cytochrome P4501A1 in human embryonic hepatic tissues during organogenesis. Biochem Pharmacol. 1995 Mar 1;49(5):717–726. doi: 10.1016/0006-2952(94)00493-6. [DOI] [PubMed] [Google Scholar]
  113. Yoo J. S., Ning S. M., Patten C. J., Yang C. S. Metabolism and activation of N-nitrosodimethylamine by hamster and rat microsomes: comparative study with weanling and adult animals. Cancer Res. 1987 Feb 15;47(4):992–998. [PubMed] [Google Scholar]
  114. Ziegler E. E., Edwards B. B., Jensen R. L., Mahaffey K. R., Fomon S. J. Absorption and retention of lead by infants. Pediatr Res. 1978 Jan;12(1):29–34. doi: 10.1203/00006450-197801000-00008. [DOI] [PubMed] [Google Scholar]
  115. Zsigmond E. K., Downs J. R. Plasma cholinesterase activity in newborns and infants. Can Anaesth Soc J. 1971 May;18(3):278–285. doi: 10.1007/BF03025463. [DOI] [PubMed] [Google Scholar]
  116. Zusterzeel P. L., Peters W. H., De Bruyn M. A., Knapen M. F., Merkus H. M., Steegers E. A. Glutathione S-transferase isoenzymes in decidua and placenta of preeclamptic pregnancies. Obstet Gynecol. 1999 Dec;94(6):1033–1038. doi: 10.1016/s0029-7844(99)00433-0. [DOI] [PubMed] [Google Scholar]
  117. Zwiener R. J., Ginsburg C. M. Organophosphate and carbamate poisoning in infants and children. Pediatrics. 1988 Jan;81(1):121–126. [PubMed] [Google Scholar]

Articles from Environmental Health Perspectives are provided here courtesy of National Institute of Environmental Health Sciences

RESOURCES