PVC and DEHP in medical devices: problems and solutions


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  • Neonatal Exchange Transfusion: 1.7 – 4.2 mg/kg DEHP (from bags) 0.36 mg/kg (0.16 – 0.68) MEHP (linear extr) Neonatal Exchange Transfusion: 1.7 – 4.2 mg/kg DEHP (from bags) 0.36 mg/kg (0.16 – 0.68) MEHP (linear extr) Neonatal Exchange Transfusion: 1.7 – 4.2 mg/kg DEHP (from bags) 0.36 mg/kg (0.16 – 0.68) MEHP (linear extr)
  • Bag photo: Farrell Valve bag, PVC-free; tubing – PVC w/DEHP PEG: percutaneous endoscopic gastrostomy
  • Bag photo: Farrell Valve bag, PVC-free; tubing – PVC w/DEHP PEG: percutaneous endoscopic gastrostomy
  • Bag photo: Farrell Valve bag, PVC-free; tubing – PVC w/DEHP PEG: percutaneous endoscopic gastrostomy
  • PVC and DEHP in medical devices: problems and solutions

    1. 1. PVC and DEHP in medical devices: problems and solutions Ted Schettler MD, MPH Science and Environmental Health Network and Boston Medical Center October 2005
    2. 2. Polyvinyl chloride (PVC) <ul><li>Vinyl chloride polymer </li></ul><ul><li>Most widely used plastic in medical products – 27% of all plastic used in 1996 </li></ul><ul><li>445 million pounds in bags, tubing, gloves, trays, catheters, etc.; also in non-medical supplies, flooring, pipes, and wall </li></ul><ul><li>coverings </li></ul>
    3. 3. PVC <ul><li>Produced with fillers, stabilizers, pigments, plasticizers, lubricants, anti-oxidants, flame retardants (dependent on application) </li></ul><ul><li>Plasticizers – phthalates; di-ethylhexyl phthalate (DEHP) used in medical devices </li></ul>
    4. 4. PVC - advantages <ul><li>Cost, flexibility, transparency, resistance to breakage </li></ul><ul><li>DEHP in PVC prolongs shelf-life of red blood cells </li></ul>
    5. 5. PVC - disadvantages <ul><li>Public health and environmental impacts of PVC production, use, and disposal </li></ul><ul><ul><li>Dioxin/furans produced during PVC production and incineration </li></ul></ul><ul><ul><li>Leaching of plasticizers, stabilizers (often metals) from landfills </li></ul></ul><ul><ul><li>Difficult to recycle </li></ul></ul><ul><li>Potential impacts on direct patient health and safety – leaching of DEHP </li></ul>
    6. 6. PVC and dioxin <ul><li>Dioxins and furans generated as by-products of manufacture of PVC feedstocks </li></ul><ul><li>Dioxins, furans, HCl formed and released when PVC is burned </li></ul><ul><ul><li>Municipal waste incinerators </li></ul></ul><ul><ul><li>Medical waste incinerators </li></ul></ul><ul><ul><li>Landfill fires </li></ul></ul>
    7. 7. Dioxin <ul><li>A “family” of chemicals, with similar structures, some more toxic than others </li></ul><ul><li>Persistent </li></ul><ul><ul><li>Environment – up to decades </li></ul></ul><ul><ul><li>Humans – half-life 7 years </li></ul></ul><ul><li>Bioaccumulative – concentrations increase as it moves up the food chain </li></ul>
    8. 8. Dioxin – low-dose health effects <ul><li>Some seen at pg-ng/kg/day levels of exposure </li></ul><ul><li>Alters levels of many enzymes, growth factors, hormones </li></ul><ul><li>Cancer </li></ul><ul><li>Reproductive/Developmental </li></ul><ul><li>Endocrine </li></ul><ul><li>Immune system </li></ul>
    9. 9. Di-ethylhexyl phthalate (DEHP) <ul><li>Phthalate Plasticizer </li></ul><ul><li>2 million tons/year </li></ul><ul><li>Ubiquitous exposure </li></ul><ul><li>General Uses </li></ul><ul><ul><li>Building materials </li></ul></ul><ul><ul><li>Clothing </li></ul></ul><ul><ul><li>Packaging </li></ul></ul><ul><ul><li>Medical Devices </li></ul></ul>
    10. 10. DEHP in Medical Devices <ul><li>Used to make PVC plastic flexible </li></ul><ul><li>20 - 40 % by weight; up to 80% in tubing. </li></ul><ul><li>Not bound to the vinyl; readily leaches. </li></ul><ul><li>Leaching increased by lipid-like content of fluids, temperature, agitation, storage time. </li></ul>
    11. 11. Sources of Medical Exposure to DEHP <ul><li>Intravenous fluids, medications </li></ul><ul><li>Exchange Transfusions </li></ul><ul><li>Replacement Transfusions </li></ul><ul><li>Extra Corporeal Membrane Oxygenation </li></ul><ul><li>Dialysis </li></ul><ul><li>Surgery; e.g. large exposures during cardiopulmonary bypass </li></ul><ul><li>Hyper-alimentation </li></ul><ul><li>Gastric Feeding, NG Tubing </li></ul><ul><li>Artificial Ventilation </li></ul>
    12. 12. DEHP developmental toxicity—animal studies <ul><li>Developmental/Reproductive Toxicity </li></ul><ul><ul><li>Skeletal, cardiovascular, eye, male reproductive tract, neural tube defects </li></ul></ul><ul><ul><li>Intrauterine death and increased post-natal death </li></ul></ul><ul><ul><li>Decreased intrauterine and postnatal growth </li></ul></ul><ul><ul><li>Alter sexual differentiation of male reproductive system </li></ul></ul><ul><ul><li>Infertility in males and females </li></ul></ul>
    13. 13. Most Sensitive System: Immature Male Reproductive Tract <ul><li>MEHP is the toxic metabolite </li></ul><ul><li>Mechanism of Action </li></ul><ul><ul><li>testosterone synthesis; interference with Leydig cell differentiation with fetal exposures </li></ul></ul><ul><li>Target Tissues </li></ul><ul><ul><li>Sertoli cells, Leydig cells </li></ul></ul><ul><ul><li>Seminiferous tubules, sperm, epididymis, penis, prostate </li></ul></ul>NTP-CERHR-DEHP-00, Oct 2000 Moore, 2001 EHP 109:229; Gray LE, NIEHS presentation
    14. 14. Most Sensitive System: Immature Male Reproductive Tract <ul><li>Impacts on developing male reproductive system are at least partially independent of peroxisome proliferation, a mechanism which is related to cancer causation in rodents. </li></ul><ul><li>Rabbits, mice, rats, guinea pigs, ferrets all show toxic impacts.  (fetal and newborn primates never studied) </li></ul><ul><li>Therefore, these studies are considered relevant to humans </li></ul>
    15. 15. Importance of route of exposure; species differences <ul><li>DEHP converted to MEHP by intestinal lipases; less rapid conversion after IV administration </li></ul><ul><li>DEHP converted to MEHP in all species </li></ul><ul><li>MEHP eliminated largely by glucuronidation (primates); further hydrolyzed by humans before glucuronidation, by hydrolysis (rodents) </li></ul>
    16. 16. Metabolic age-related differences impacting toxicity of DEHP <ul><li>Fetus and infant have reduced glucuronidation capacity compared to adult </li></ul><ul><li>Infants have higher gastric lipase activity than older children/adults </li></ul><ul><li>Children absorb more DEHP from the intestinal tract than adults </li></ul>
    17. 17. Magnitude of Neonatal Exposure (General population exposure: 0.003 – 0.030 mg/kg/day) <ul><li>Neonatal Exchange Transfusion </li></ul><ul><ul><li>1.8 mg/kg/exch (0.84 – 3.3) DEHP </li></ul></ul><ul><li>Replacement Transfusion </li></ul><ul><ul><li>0.3 mg/kg/tx (0.14-0.72) DEHP </li></ul></ul><ul><li>ECMO (depending on circuit and assumptions) </li></ul><ul><ul><li>0.0 – 140 mg/kg DEHP </li></ul></ul>Sjoberg, 1985. Eur J Clin Invest 15:430 Sjoberg, 1985. Transfusion 25:424 Karle, 1997. Crit Care Med 25:696 Levels in children with these exposures exceed the NOAEL in animal studies
    18. 18. NTP panel – Center for the Evaluation of Risks to Human Reproduction <ul><li>&quot;serious concern&quot; for the possibility of adverse effects on the developing reproductive tract of male infants exposed to very high levels of DEHP that might be associated with intensive medical procedures such as those used in critically ill infants. </li></ul><ul><li>&quot;concern&quot; that, if infants and toddlers are exposed to levels of DEHP substantially higher than adults, adverse effects might occur in the developing male reproductive tract. </li></ul>
    19. 19. FDA safety assessment of DEHP <ul><li>Considered species differences, pharmaco- kinetics, route of exposure </li></ul><ul><li>Developed a “tolerable intake” (TI) for oral and parenteral exposure, below which no adverse effects expected </li></ul><ul><li>TI based only on developing testes as the most sensitive endpoint </li></ul>
    20. 20. FDA safety assessment (cont’d) <ul><li>FDA derived a “tolerable intake” (TI) for DEHP via oral and parenteral routes </li></ul><ul><li>TI calculations based on NOAELs and LOAELs from numerous animal studies of testicular toxicity </li></ul>
    21. 21. Tolerable intake (TI) for DEHP <ul><li>0.6 mg DEHP/kg/day for parenteral exposures </li></ul><ul><li>0.04 mg DEHP/kg/day for oral exposures </li></ul><ul><li>TI/dose ratio identifies procedures or treatments that are likely to result in an exposure that exceeds the TI </li></ul>
    22. 22. adult neonate 0.02 22.6 exchange transfusion 0.04 14 0.2 3.0 ECMO 0.3 0.14 < 1.0 Enteral nutrition 0.2 2.5 5 0.13 TPN (lipid) 20 0.03 4 0.15 IV drugs w/vehicles 20 0.03 120 0.005 IV:cryst TI/dose DEHP dose TI/dose DEHP dose, mg/kg/day, upper bound
    23. 23. FDA public health notification and guidance <ul><li>Recommends the use of alternatives to DEHP-containing products for those procedures where exposures may be excessive </li></ul><ul><li>Recommends reformulation of products to decrease/eliminate DEHP exposures </li></ul><ul><li>Recommends labeling of DEHP-containing products </li></ul>
    24. 24. Additional concerns <ul><li>Breast milk infusion from non-PVC bag or syringe through DEHP-containing tubing </li></ul><ul><li>Simultaneous exposures from multiple sources </li></ul><ul><ul><li>A 4 kg infant in NICU could receive approx </li></ul></ul><ul><ul><li>3 mg DEHP/kg/day for weeks or months </li></ul></ul><ul><ul><li>TI/dose approx 0.05 </li></ul></ul><ul><li>Fetal exposures—DEHP/MEHP in cord blood </li></ul>
    25. 25. Additional concerns <ul><li>Background exposures to DEHP approx </li></ul><ul><li>3-30 micrograms/kg/day, up to ¾ of the oral TI (diet the largest source in gen’l population) </li></ul><ul><li>Exposure to multiple phthalates, in addn to DEHP, that have cumulative impacts </li></ul><ul><li>(CDC’s exposure assessments confirm the ubiquity of phthalate exposures.) </li></ul><ul><li>www.cdc.gov/exposurereport </li></ul>
    26. 26. Other effects, DEHP (FDA report, annex D) <ul><li>DEHP causes platelet aggregation and complement activation </li></ul><ul><li>Microemboli during ECMO or cardio-pulmonary bypass may be related to DEHP </li></ul><ul><li>Drug loss by binding to surface of PVC tubing or bags </li></ul>
    27. 27. Urinary levels of the DEHP metabolite, MEHP, in NICU infants Ronald Green, MD, MPH (1); Russ Hauser, MD, MPH, ScD (1); Antonia Calafat, PhD (2); Jennifer Weuve, MPH, ScD (1); Ted Schettler, MD, MPH (3); Steven Ringer, MD, PhD (4); Kenneth Huttner, MD (5); Howard Hu, MD, MPH, ScD (1,6) To assess neonatal exposure to DEHP containing medical devices encountered in the course of ICU care and measure the urinary metabolite MEHP.
    28. 28. <ul><li>Convenience sample of (54) infants enrolled from two Level III Boston hospital nurseries; </li></ul><ul><li>Infants were in the NICU at least 3 days before observation; </li></ul><ul><li>Exposure classification: LOW, MEDIUM, and HIGH DEHP exposure classification categories were determined prior to analysis </li></ul>Methods
    29. 29. <ul><li>LOW exposure: primarily bottle and/or gavage feedings; </li></ul><ul><li>MEDIUM exposure: enteral feedings, intravenous (IV) hyperalimentation, and/or nasal continuous positive airway pressure (CPAP); </li></ul><ul><li>HIGH exposure: umbilical vessel catheterization, endotracheal intubation, IV hyperalimentation and an indwelling gavage tube </li></ul>Exposure classification
    30. 30. Median and IQR of urinary MEHP, by class of DEHP exposure, adjusted for sex and institution. 0 20 40 60 80 100 120 140 160 180 200 Low Medium High MEHP ng/ml urine median DEHP exposure class 75 th percentile 25th percentile DEHP Exposure Class
    31. 31. Potential responses to DEHP concerns <ul><li>Labeling of DEHP-containing products </li></ul><ul><li>Preferential purchasing policies; alternatives available for most products </li></ul><ul><li>Heparin coated PVC tubing reduces platelet aggregation and complement activation </li></ul><ul><li>Minimize blood storage time in PVC bags </li></ul><ul><li>Minimize solution agitation and warming </li></ul><ul><li>Follow existing label instructions for drug delivery (note that alternative tubing less readily available than alternative bags) </li></ul>
    32. 32. PVC in Hospitals: Disposable Medical Products <ul><li> Percent of PVC Disposable Products </li></ul><ul><li>Tubing 43.0% </li></ul><ul><li>Bags 42.5% </li></ul><ul><li>Gloves 12.5% </li></ul><ul><li>Trays for Kits 1.5% </li></ul><ul><li>Catheters 0.5% </li></ul>Source: Schecter, 1996
    33. 33. History of Alternatives to PVC <ul><li>1974-’75: EVA TPN bag and polyolefin platelet bag -- Baxter </li></ul>1992: Citrate-softened PVC red blood cell bag -- Baxter 1980s: Polyolefin/polyester laminate bag for IV solutions -- B.Braun 1970s: Polyurethane and s ilicone umbilical vessel catheters and nasogastric tubes
    34. 34. Options to DEHP-containing Medical Devices <ul><li>“ DEHP-free” / “Non-DEHP” -- PVC without DEHP </li></ul><ul><ul><li>Alternative plasticizers – citrates, trimellitates, adipates – can leach out </li></ul></ul><ul><ul><li>Poor toxicological data on alternatives (some share toxicity features of phthalates) </li></ul></ul><ul><li>“ PVC-free” / “Non-PVC” -- No DEHP, No PVC </li></ul><ul><ul><li>PVC-free alternatives are inherently flexible, no need for plasticizers </li></ul></ul><ul><ul><li>Materials include: polypropylene, polyethylene, ethylene vinyl acetate (EVA), silicone, polyurethane </li></ul></ul>
    35. 35. <ul><li>Staff initiated process to identify DEHP products in NICU, including evaluation of alternatives </li></ul><ul><li>System-wide switch to non-DEHP products: </li></ul><ul><ul><li>umbilical vessel catheters </li></ul></ul><ul><ul><li>PICC lines </li></ul></ul><ul><ul><li>enteral feeding products </li></ul></ul>Case Studies <ul><li>2002 FDA public health notification triggered action with ICN staff </li></ul><ul><li>Internal PVC/DEHP audit of NICU shelves and identified comparable alternatives </li></ul><ul><li>Switched out virtually all products and replaced with non-DEHP alternatives </li></ul>
    36. 36. European Demand - Vienna Hospital Association <ul><li>Glanzing Pediatric and Preyer Pediatric Hospitals </li></ul><ul><li>Glanzing Neonatal Unit – nearly PVC-free </li></ul><ul><ul><li>Almost all invasive PVC products eliminated, including nasogastric tubes and umbilical vessel catheters </li></ul></ul><ul><ul><li>Most non-invasive PVC products eliminated, including IV </li></ul></ul><ul><li>Phase out use of PVC products Hospital-Wide – 50% of PVC products eliminated </li></ul>
    37. 37. Enteral Feeding <ul><li>VIASYS Healthcare (formerly CORPAK ) </li></ul><ul><ul><li>PVC-free bags: nylon/EVA/polypropylene </li></ul></ul><ul><ul><li>PVC-free tubes (gastrostomy, nasoenteric, PEG): silicone, polyurethane </li></ul></ul>VIASYS: Farrell valve Kendall: DEHP-free Kangaroo Set Arrow Int’l: silicone feeding tube <ul><li>Arrow International (formerly Klein Baker) </li></ul><ul><ul><li>PVC-free feeding tubes for neonates: silicone </li></ul></ul><ul><li>Tyco (Kendall) Healthcare </li></ul><ul><ul><li>DEHP-free enteral feeding sets </li></ul></ul><ul><ul><li>PVC-free tubes: silicone, polyurethane </li></ul></ul>Other Manufacturers: Bard, Ross, Utah Medical, Vygon, Zevex
    38. 38. Total Parenteral Nutrition (TPN) <ul><li>PVC-free TPN bags: Ethylene Vinyl Acetate </li></ul><ul><ul><li>Baxter Healthcare </li></ul></ul><ul><ul><li>Baxa Corp. </li></ul></ul>Baxa Corp . Baxter Compounding System
    39. 39. IV Products <ul><li>IV Containers </li></ul>DEHP-free: --many manufacturers Medex Admin Sets PVC-free: -- Medex, Inc. (polyethylene) -- Natvar (polyurethane) PVC-free: -- B Braun (PP/PE/Polyester) B Braun <ul><li>EXCEL® and PAB® IV Containers </li></ul><ul><li>Innovative PVC-Free and DEHP-Free plastic IV containers </li></ul><ul><li>… </li></ul>
    40. 40. Market Trends <ul><li>PVC-free </li></ul><ul><ul><li>Alternative plastics to PVC are the material of choice for bags </li></ul></ul><ul><ul><li>Better performance: more compatible with a wider range of drugs, less concern with leaching </li></ul></ul><ul><li>Hospira webpage … Nutrimix ® Dual Chamber Flexible Container > TPN: </li></ul><ul><li>... </li></ul><ul><li>… </li></ul><ul><li>Non-DEHP containers and sets available </li></ul><ul><li>DEHP-free Products Widely Available </li></ul><ul><ul><li>Most vendors now have clearly labeled DEHP-free product lines </li></ul></ul><ul><ul><li>Especially for tubing applications </li></ul></ul>Hospira
    41. 41. Performance of PVC-free Alternatives <ul><li>Safety </li></ul><ul><li>PVC-free plastics inherently flexible – no plasticizers </li></ul><ul><li>Chlorine-free w/exception of neoprene gloves </li></ul><ul><li>PVC-free plastics compatible with broader range of drugs </li></ul><ul><li>Performance </li></ul><ul><li>Clear, flexible, often steam sterilizable </li></ul><ul><li>Costs </li></ul><ul><li>Bags : cost-competitive due to “downgauging” </li></ul><ul><li>Tubing : can cost more, but may have longer use life </li></ul><ul><li>Gloves : cost-competitive at large volume </li></ul>
    42. 42. Environmental Spectrum of Plastics
    43. 43. Resource s <ul><li>Sustainable Hospitals Project </li></ul><ul><ul><li>www.sustainablehospitals.org </li></ul></ul>Health Care Without Harm www.noharm.org