Archives of Toxicology

, Volume 79, Issue 2, pp 63–73 | Cite as

Elevated internal exposure of children in simulated acute inhalation of volatile organic compounds: effects of concentration and duration

  • Klaus Abraham
  • Hans Mielke
  • Wilhelm Huisinga
  • Ursula Gundert-Remy
Original Investigation


When deriving health-based exposure limits in recent years, increasing attention has been drawn to susceptible subpopulations, in particular to children. We investigated the differences in kinetics between children and adults during inhalation of styrene as a typical category-3 volatile organic compound (VOC), i.e., a gas with a low reactivity and low water solubility allowing a high rate of alveolar absorption. Internal exposure was simulated using a physiologically based kinetic model over a broad range of airborne concentrations (1–1000 ppm) and for an exposure time of up to 8 h according to the scenario in the acute exposure guideline level (AEGL) program. Age-specific anatomical and physiological parameters and compound-specific data was derived from the literature. The calculated concentrations in arterial blood are higher in children than in adults, and are highest in the newborn. For an 8-h exposure to low concentrations, the calculated arterial concentration in the newborn is higher by a factor of 2.3 than in the adult. This is due mainly to the relatively high ventilation rate and the immature metabolism. With increasing airborne concentration, the ratio of arterial concentrations (newborn/adult) increases to a maximum of 3.8 at 130 ppm in ambient air, and declines with further increments of concentration to a value of 1.7. This is because the metabolism of the newborn becomes non-linear at lower concentrations than in adults. At high concentrations, metabolism is saturated in both age groups. For shorter exposures, the dose dependency of the concentration ratios (newborn/adult) is less pronounced. This is the first article to show that the intraspecies assessment factor may vary with concentration and duration of exposure.


Children Inhalation Kinetics Model Risk assessment Styrene 


Acknowledgements. This work was supported by European Union (contract no. EVG1-CT-2002-00071) within Fifth Framework Program, and supported by Deutsche Forschungsgemeinschaft (DFG) as a project within DFG Research Center “Mathematics for key technologies”, Berlin, Germany.


  1. Abraham K, Mielke H, Huisinga W, Gundert-Remy U (2005) Internal exposure of children by acute inhalation of volatile organic compounds: the influence of chemical properties on the child/adult concentration ratio. Basic Clin Pharmacol Toxicol 96: in pressGoogle Scholar
  2. Alverson DC, Eldridge M, Dillon T, Yabek SM, Berman W (1982) Noninvasive pulsed Doppler determination of cardiac output in neonates and children. J Pediatr 101:46–50PubMedGoogle Scholar
  3. Alverson DC, Aldrich M, Angelus P, Backstrom C, Werner S (1987) Longitudinal trends in left ventricular cardiac output in healthy infants in the first year of life. J Ultrasound Med 6:519–524PubMedGoogle Scholar
  4. Chiron C, Raynaud C, Maziere B, Zilbovicius M, Laflamme L, Masure MC, Dulac O, Bourguignon M, Syrota A (1992) Changes in regional cerebral blood flow during brain maturation in children and adolescents. J Nucl Med 33:696–703PubMedGoogle Scholar
  5. Cohen Hubal EA, Sheldon LS, Burke JM, McCurdy TR, Berry MR, Rigas ML, Zartarian VG, Freeman NC (2000) Children’s exposure assessment: a review of factors influencing children’s exposure, and the data available to characterize and assess that exposure. Environ Health Perspect 108:475–486Google Scholar
  6. Cresteil T (1998) Onset of xenobiotic metabolism in children: toxicological implications. Food Addit Contam 15 (Suppl):45–51PubMedGoogle Scholar
  7. Csanady GA, Mendrala AL, Nolan RJ, Filser JG (1994) A physiologic pharmacokinetic model for styrene and styrene-7,8-oxide in mouse, rat and man. Arch Toxicol 68:143–157CrossRefPubMedGoogle Scholar
  8. Dourson M, Charnley G, Scheuplein R (2002) Differential sensitivity of children and adults to chemical toxicity. II. Risk and regulation. Regul Toxicol Pharmacol 35:448–467CrossRefPubMedGoogle Scholar
  9. Evans JM, Hogg MI, Rosen M (1977) Measurement of carbon dioxide output, alveolar carbon dioxide concentration and alveolar ventilation in the neonate. Br J Anaesth 49:453–456PubMedGoogle Scholar
  10. Fiserova-Bergerova V (1983) Modeling of inhalation exposure to vapors: uptake, distribution, and elimination, vols I and II. CRC Press, Boca Raton, FloridaGoogle Scholar
  11. Ginsberg G, Slikker W Jr, Bruckner J, Sonawane B (2004) Incorporating children’s toxicokinetics into a risk framework. Environ Health Perspect 112:272–283PubMedGoogle Scholar
  12. Grunert D, Schoning M, Rosendahl W (1990) Renal blood flow and flow velocity in children and adolescents: duplex Doppler evaluation. Eur J Pediatr 149:287–292PubMedGoogle Scholar
  13. Hattis D, Ginsberg G, Sonawane B, Smolenski S, Russ A, Kozlak M, Goble R (2003) Differences in pharmacokinetics between children and adults. II. Children’s variability in drug elimination half-lives and in some parameters needed for physiologically-based pharmacokinetic modeling. Risk Anal 23:117–142CrossRefPubMedGoogle Scholar
  14. Hill JR, Rahimtulla KA (1965) Heat balance and the metabolic rate of newborn babies. J Physiol 180:239–265PubMedGoogle Scholar
  15. ICRP Publication 89 (2003) Basic anatomical and physiological data for use in radiological protection: reference values. Elsevier, OxfordGoogle Scholar
  16. Johanson G (1991) Modelling of respiratory exchange of polar solvents. Ann Occup Hyg 35:323–339PubMedGoogle Scholar
  17. Kerr AA (1976) Dead space ventilation in normal children and children with obstructive airways disease. Thorax 31:63–69PubMedGoogle Scholar
  18. Lagneaux D, Mossay C, Geubelle F, Christiaens G (1988) Alveolar data in healthy, awake neonates during spontaneous ventilation: a preliminary investigation. Pediatr Pulmonol 5:225–231PubMedGoogle Scholar
  19. Layton DW (1993) Metabolically consistent breathing rates for use in dose assessments. Health Phys 64:23–36PubMedGoogle Scholar
  20. Lees MH, Way RC, Ross BB (1967) Ventilation and respiratory gas transfer of infants with increased pulmonary blood flow. Pediatrics 40:259–271PubMedGoogle Scholar
  21. Leggett RW, Williams LR (1995) A proposed blood circulation model for Reference Man. Health Phys 69:187–201PubMedGoogle Scholar
  22. Meulenberg CJ, Vijverberg HP (2000) Empirical relations predicting human and rat tissue: air partition coefficients of volatile organic compounds. Toxicol Appl Pharmacol 165:206–216CrossRefPubMedGoogle Scholar
  23. Nelson NM, Prod’hom LS, Cherry RB, Lipsitz PJ, Smith CA (1962) Pulmonary function in the newborn infant. I. Methods: Ventilation and gaseous metabolism. Pediatrics 30:963–974PubMedGoogle Scholar
  24. Pelekis M, Gephart LA, Lerman SE (2001) Physiological-model-based derivation of the adult and child pharmacokinetic intraspecies uncertainty factors for volatile organic compounds. Regul Toxicol Pharmacol 33:12–20CrossRefPubMedGoogle Scholar
  25. Pierce CH, Becker CE, Tozer TN, Owen DJ, So Y (1998) Modeling the acute neurotoxicity of styrene. J Occup Environ Med 40:230–240CrossRefPubMedGoogle Scholar
  26. Polgar G, Weng TR (1979) The functional development of the respiratory system. From the period of gestation to adulthood. Am Rev Respir Dis 120:625–695PubMedGoogle Scholar
  27. Price K, Haddad S, Krishnan K (2003) Physiological modeling of age-specific changes in the pharmacokinetics of organic chemicals in children. J Toxicol Environ Health A 66:417–433CrossRefPubMedGoogle Scholar
  28. Ramsey JC, Andersen ME (1984) A physiologically based description of the inhalation pharmacokinetics of styrene in rats and humans. Toxicol Appl Pharmacol 73:159–175CrossRefPubMedGoogle Scholar
  29. Renwick AG, Dorne JL, Walton K (2000) An analysis of the need for an additional uncertainty factor for infants and children. Regul Toxicol Pharmacol 31:286–296CrossRefPubMedGoogle Scholar
  30. Sandberg K, Sjoqvist BA, Hjalmarson O, Olsson T (1984) Analysis of alveolar ventilation in the newborn. Arch Dis Child 59:542–547PubMedGoogle Scholar
  31. Sarangapani R, Gentry PR, Covington TR, Teeguarden JG, Clewell HJ (2003) Evaluation of the potential impact of age- and gender-specific lung morphology and ventilation rate on the dosimetry of vapors. Inhal Toxicol 15:987–1016PubMedGoogle Scholar
  32. Scheuplein R, Charnley G, Dourson M (2002) Differential sensitivity of children and adults to chemical toxicity. I. Biological basis. Regul Toxicol Pharmacol 35:429–447CrossRefPubMedGoogle Scholar
  33. Schöning M, Hartig B (1996) Age dependence of total cerebral blood flow volume from childhood to adulthood. J Cereb Blood Flow Metab 16:827–833PubMedGoogle Scholar
  34. US-AEGL committee (2001) Standing operating procedures for developing acute exposure guideline levels for hazardous chemicals. National Academy Press, Washington DCGoogle Scholar
  35. US-EPA (1994) Methods for derivation of inhalation reference concentrations and application of inhalation dosimetry (doc. no. EPA/600/8-90/066F). Research Triangle Park, North CarolinaGoogle Scholar
  36. Vieira I, Sonnier M, Cresteil T (1996) Developmental expression of CYP2E1 in the human liver. Hypermethylation control of gene expression during the neonatal period. Eur J Biochem 238:476–483CrossRefPubMedGoogle Scholar
  37. Visser MO, Leighton JO, van de Bor M, Walther FJ (1992) Renal blood flow in neonates: quantification with color flow and pulsed Doppler US. Radiology 183:441–444PubMedGoogle Scholar
  38. Williams LR, Leggett RW (1989) Reference values for resting blood flow to organs of man. Clin Phys Physiol Meas 10:187–217CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  • Klaus Abraham
    • 1
  • Hans Mielke
    • 1
  • Wilhelm Huisinga
    • 2
  • Ursula Gundert-Remy
    • 1
  1. 1.Federal Institute for Risk AssessmentBerlinGermany
  2. 2.Department of Mathematics and Computer ScienceFree University BerlinBerlinGermany

Personalised recommendations