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Phthalates and critically ill neonates: device-related exposures and non-endocrine toxic risks

Journal of Perinatology volume 34, pages 892–897 (2014)Cite this article

Subjects

Abstract

Objective:

To assess the types and magnitudes of non-endocrine toxic risks to neonates associated with medical device-related exposures to di(2-ethylhexyl)phthalate (DEHP).

Study design:

Dose-response thresholds for DEHP toxicities were determined from published data, as were the magnitudes of DEHP exposures resulting from neonatal contact with polyvinyl chloride (PVC) devices. Standard methods of risk assessment were used to determine safe levels of DEHP exposure in neonates, and hazard quotients were calculated for devices individually and in aggregate.

Result:

Daily intake of DEHP for critically ill preterm infants can reach 16 mg/kg per day, which is on the order of 4000 and 160,000 times higher than desired to avoid reproductive and hepatic toxicities, respectively. The non-endocrine toxicities of DEHP are similar to complications experienced by preterm neonates.

Conclusion:

DEHP exposures in neonatal intensive care are much higher than estimated safe limits, and might contribute to common early and chronic complications of prematurity. Concerns about phthalates should be expanded beyond endocrine disruption.

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References

  1. Phthalates and Cumulative Risk Assessment—The Tasks Ahead Committee on the Health Risks of Phthalates National Research Council of the National Academies. The National Academies Press: Washington, DC 2008.

  2. SCENIHR Opinion on the Safety of Medical Devices Containing DEHP-Plasticized PVC or Other Plasticizers on Neonates and Other Groups Possibly at Risk Scientific Committee on Emerging and Newly Identified Health Risks (SCENIHR). European Commission; Health and Consumer Protection Directorate-General, Brussels, Belgium, 2008.

  3. Toxicity Review of Di(2-ethylhexyl) Phthalate (DEHP). United States Consumer Product Safety Commission, Bethesda, MD, 2010.

  4. Green R, Hauser R, Calafat AM, Weuve J, Schettler T, Ringer S et al. Use of di(2-ethylhexyl) phthalate-containing medical products and urinary levels of mono(2-ethylhexyl) phthalate in neonatal intensive care unit infants. Environ Health Perspect 2005; 113 (9): 1222–1225.

    Article  CAS  Google Scholar 

  5. Weuve J, Sanchez BN, Calafat AM, Schettler T, Green RA, Hu H et al. Exposure to phthalates in neonatal intensive care unit infants: urinary concentrations of monoesters and oxidative metabolites. Environ Health Perspect 2006; 114 (9): 1424–1431.

    Article  CAS  Google Scholar 

  6. Su PH, Chang YZ, Chang HP, Wang SL, Haung HI, Huang PC et al. Exposure to di(2-ethylhexyl) phthalate in premature neonates in a neonatal intensive care unit in Taiwan. Pediatr Crit Care Med 2012; 13 (6): 671–677.

    Article  Google Scholar 

  7. Calafat AM, Needham LL, Silva MJ, Lambert G. . Exposure to di-(2-ethylhexyl) phthalate among premature neonates in a neonatal intensive care unit. Pediatrics 2004; 113 (5): e429–e434.

    Article  Google Scholar 

  8. Bustamante-Montes LP, Hernandez-Valero MA, Flores-Pimentel D, Garcia-Fabila M, Amaya-Chavez A, Barr DB et al. Prenatal exposure to phthalates is associated with decreased anogenital distance and penile size in male newborns. J Dev Orig Health Dis 2013; 4 (4): 300–306.

    Article  CAS  Google Scholar 

  9. Swan SH. . Environmental phthalate exposure in relation to reproductive outcomes and other health endpoints in humans. Environ Res 2008; 108 (2): 177–184.

    Article  CAS  Google Scholar 

  10. US Environmental Protection Agency. Glossary of Key Terms www.epa.gov/ttn/atw/natamain/gloss1.html. Accessed 2 May 2014.

  11. Vetrano AM, Laskin DL, Archer F, Syed K, Gray JP, Laskin JD et al. Inflammatory effects of phthalates in neonatal neutrophils. Pediatr Res 2010; 68 (2): 134–139.

    Article  CAS  Google Scholar 

  12. Gourlay T, Samartzis I, Stefanou D, Taylor K. . Inflammatory response of rat and human neutrophils exposed to di-(2-ethyl-hexyl)-phthalate-plasticized polyvinyl chloride. Artif Organs 2003; 27 (3): 256–260.

    Article  CAS  Google Scholar 

  13. Rael LT, Bar-Or R, Ambruso DR, Mains CW, Slone DS, Craun ML et al. Phthalate esters used as plasticizers in packed red blood cell storage bags may lead to progressive toxin exposure and the release of pro-inflammatory cytokines. Oxid Med Cell Longev 2009; 2 (3): 166–171.

    Article  Google Scholar 

  14. Jepsen KF, Abildtrup A, Larsen ST. . Monophthalates promote IL-6 and IL-8 production in the human epithelial cell line A549. Toxicol In Vitro 2004; 18 (3): 265–269.

    Article  CAS  Google Scholar 

  15. Hansen JS, Larsen ST, Poulsen LK, Nielsen GD. . Adjuvant effects of inhaled mono-2-ethylhexyl phthalate in BALB/cJ mice. Toxicology 2007; 232 (1-2): 79–88.

    Article  CAS  Google Scholar 

  16. Kimber I, Dearman RJ. . An assessment of the ability of phthalates to influence immune and allergic responses. Toxicology 2010; 271 (3): 73–82.

    Article  CAS  Google Scholar 

  17. Thor Larsen S, My Lund R, Damgård Nielsen G, Thygesen P, Melchior Poulsen O . Di-(2-ethylhexyl) phthalate possesses an adjuvant effect in a subcutaneous injection model with BALB/c mice. Toxicol Lett 2001; 125: 11–18.

    Article  CAS  Google Scholar 

  18. Larsen ST, Nielsen GD. . The adjuvant effect of di-(2-ethylhexyl) phthalate is mediated through a PPARalpha-independent mechanism. Toxicol Lett 2007; 170 (3): 223–228.

    Article  CAS  Google Scholar 

  19. Larsen ST, Hansen JS, Hansen EW, Clausen PA, Nielsen GD. . Airway inflammation and adjuvant effect after repeated airborne exposures to di-(2-ethylhexyl)phthalate and ovalbumin in BALB/c mice. Toxicology 2007; 235 (1-2): 119–129.

    Article  CAS  Google Scholar 

  20. Kambia N, Dine T, Gressier B, Frimat B, Cazin JL, Luyckx M et al. Correlation between exposure to phthalates and concentrations of malondialdehyde in infants and children undergoing cyclic parenteral nutrition. J Parenter Enteral Nutr 2011; 35 (3): 395–401.

    Article  CAS  Google Scholar 

  21. Magliozzi R, Nardacci R, Scarsella G, Di Carlo V, Stefanini S. . Effects of the plasticiser DEHP on lung of newborn rats: catalase immunocytochemistry and morphometric analysis. Histochem Cell Biol 2003; 120 (1): 41–49.

    Article  CAS  Google Scholar 

  22. Rosicarelli B, Stefanini S. . DEHP effects on histology and cell proliferation in lung of newborn rats. Histochem Cell Biol 2009; 131 (4): 491–500.

    Article  CAS  Google Scholar 

  23. Subotic U, Hannmann T, Kiss M, Brade J, Breitkopf K, Loff S. . Extraction of the plasticizers diethylhexylphthalate and polyadipate from polyvinylchloride nasogastric tubes through gastric juice and feeding solution. J Pediatr Gastroenterol Nutr 2007; 44 (1): 71–76.

    Article  CAS  Google Scholar 

  24. von Rettberg H, Hannman T, Subotic U, Brade J, Schaible T, Waag KL et al. Use of di(2-ethylhexyl)phthalate-containing infusion systems increases the risk for cholestasis. Pediatrics 2009; 124 (2): 710–716.

    Article  Google Scholar 

  25. Loff PD, Subotic U, Oulmi-Kagermann J, Kranzlin B, Reinecke MF, Staude C. . Diethylhexylphthalate extracted by typical newborn lipid emulsions from polyvinylchloride infusion systems causes significant changes in histology of rabbit liver. JPEN J Parenter Enteral Nutr 2007; 31 (3): 188–193.

    Article  CAS  Google Scholar 

  26. Smith CA, Macdonald A, Holahan MR. . Acute postnatal exposure to di(2-ethylhexyl) phthalate adversely impacts hippocampal development in the male rat. Neuroscience 2011; 193: 100–108.

    Article  CAS  Google Scholar 

  27. Keeley RJ, Wartman BC, Hausler AN, Holahan MR. . Effect of juvenile pretraining on adolescent structural hippocampal attributes as a substrate for enhanced spatial performance. Learn Mem 2010; 17 (7): 344–354.

    Article  Google Scholar 

  28. Zei D, Pascarella A, Barrese C, Pantalone S, Stefanini S. . DEHP effects on retinal vessels in newborn rats: a qualitative and quantitative analysis. Histochem Cell Biol 2009; 132 (5): 567–575.

    Article  CAS  Google Scholar 

  29. Sampson J, De Korte D. . DEHP-plasticised PVC: relevance to blood services. Transfus Med 2010; 21 (2): 73–83.

    Article  Google Scholar 

  30. Deepa Devi KV, Manoj Kumar V, Arun P, Santhosh A, Padmakumaran Nair KG, Lakshmi LR et al. Increased lipid peroxidation of erythrocytes in blood stored in polyvinyl chloride blood storage bags plasticized with di-[2-ethyl hexyl] phthalate and effect of antioxidants. Vox Sang 1998; 75 (3): 198–204.

    Article  CAS  Google Scholar 

  31. Loff S, Kabs F, Witt K, Sartoris J, Mandl B, Niessen KH et al. Polyvinylchloride infusion lines expose infants to large amounts of toxic plasticizers. J Pediatr Surg 2000; 35 (12): 1775–1781.

    Article  CAS  Google Scholar 

  32. Loff S, Kabs F, Subotic U, Schaible T, Reinecke F, Langbein M. . Kinetics of diethylhexyl-phthalate extraction from polyvinylchloride-infusion lines. JPEN J Parenter Enteral Nutr 2002; 26 (5): 305–309.

    Article  CAS  Google Scholar 

  33. Latini G, De Felice C, Del Vecchio A, Barducci A, Ferri M, Chiellini F. . Di-(2-ethylhexyl)phthalate leakage and color changes in endotracheal tubes after application in high-risk newborns. Neonatology 2009; 95 (4): 317–323.

    Article  CAS  Google Scholar 

  34. Chiellini F, Ferri M, Latini G. . Physical-chemical assessment of di-(2-ethylhexyl)-phthalate leakage from poly(vinyl chloride) endotracheal tubes after application in high risk newborns. Int J Pharm 2011; 409: 57–61.

    Article  CAS  Google Scholar 

  35. Peterson J, Johnson N, Deakins K, Wilson-Costello D, Jelovsek JE, Chatburn R. . Accuracy of the 7-8-9 rule for endotracheal tube placement in the neonate. J Perinatol 2006; 26 (6): 333–336.

    Article  CAS  Google Scholar 

  36. Weight of a conventional uncuffed 3.5 mm internal diameter endotracheal tube (Mallinckrodt, Covidien LLC, Mansfield, MA). Measured by Mallow EB; unpublished data, 2012.

  37. Roth B, Herkenrath P, Lehmann HJ, Ohles HD, Homig HJ, Benz-Bohm G et al. Di-(2-ethylhexyl)-phthalate as plasticizer in PVC respiratory tubing systems: indications of hazardous effects on pulmonary function in mechanically ventilated, preterm infants. Eur J Pediatr 1988; 147 (1): 41–46.

    Article  CAS  Google Scholar 

  38. Cirgin Ellett ML, Cohen MD, Perkins SM, Smith CE, Lane KA, Austin JK. . Predicting the insertion length for gastric tube placement in neonates. J Obstet Gynecol Neonatal Nurs 2011; 40 (4): 412–421.

    Article  Google Scholar 

  39. Code of Federal Regulations—Title 16. Commercial Practices; Chapter 2: Consumer Product Safety Commission; Subchapter C: Federal Hazardous Substances Act Regulations. 16 CFR 1500.135—Summary of guidelines for determining chronic toxicity. www.gpo.gov/fdsys/granule/CFR-2012-title16-vol2/CFR-2012-title16-vol2-sec1500-135. Accessed 21 August 2014.

  40. Pesticides in the Diets of Infants and Children. Committee on Pesticides in the Diets of Infants and Children National Research Council of the National Academies. The National Academies Press: Washington, DC, 1993.

  41. A Review of the Reference Dose and Reference Concentration Processes (EPA/630/P-02/002F) Prepared for the Risk Assessment Forum by the Reference Dose/Reference Concentration (RfD/RfC) Technical Panel. Environmental Protection Agency (EPA): US, 2002.

  42. Narendran V, Donovan EF, Hoath SB, Akinbi HT, Steichen JJ, Jobe AH. . Early bubble CPAP and outcomes in ELBW preterm infants. J Perinatol 2003; 23 (3): 195–199.

    Article  Google Scholar 

  43. Bornehag CG, Nanberg E. . Phthalate exposure and asthma in children. Int J Androl 2010; 33 (2): 333–345.

    Article  CAS  Google Scholar 

  44. Cho SC, Bhang SY, Hong YC, Shin MS, Kim BN, Kim JW et al. Relationship between environmental phthalate exposure and the intelligence of school-age children. Environ Health Perspect 2010; 118 (7): 1027–1032.

    Article  CAS  Google Scholar 

  45. Swan SH, Liu F, Hines M, Kruse RL, Wang C, Redmon JB et al. Prenatal phthalate exposure and reduced masculine play in boys. Int J Androl 2010; 33 (2): 259–269.

    Article  CAS  Google Scholar 

  46. Van Vliet ED, Reitano EM, Chhabra JS, Bergen GP, Whyatt RM. . A review of alternatives to di (2-ethylhexyl) phthalate-containing medical devices in the neonatal intensive care unit. J Perinatol 2011; 31 (8): 551–560.

    Article  CAS  Google Scholar 

  47. Consumer Product Safety Improvement Act of 2008. 110th Congress. Public Law 110-314, 14 August 2008.

  48. France Law 2012-1442, passed 24 December 2012. Journal Officiel de la Republique Francaise (Official Journal of the French Republic), 2012.

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Acknowledgements

The authors gratefully acknowledge Thomas A. Burke for his advice on the conceptual design and development of this study.

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  1. Johns Hopkins Bloomberg School of Public Health, Risk Sciences and Public Policy Institute, Baltimore, MD, USA

    E B Mallow & M A Fox

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Correspondence to E B Mallow.

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Mallow, E., Fox, M. Phthalates and critically ill neonates: device-related exposures and non-endocrine toxic risks. J Perinatol 34, 892–897 (2014). https://doi.org/10.1038/jp.2014.157

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