PVC and DEHP in medical devices problems and solutions - PowerPoint

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					PVC and DEHP in medical
  devices: problems and
       Ted Schettler MD, MPH
  Science and Environmental Health
       Boston Medical Center

             October 2005
      Polyvinyl chloride (PVC)

 Vinyl chloride polymer
 Most widely used plastic in medical products –
  27% of all plastic used in 1996
 445 million pounds in bags, tubing, gloves,
  trays, catheters, etc.; also in non-medical
  supplies, flooring, pipes, and wall
   Produced with fillers, stabilizers, pigments,
    plasticizers, lubricants, anti-oxidants, flame
    retardants (dependent on application)

   Plasticizers – phthalates; di-ethylhexyl
    phthalate (DEHP) used in medical devices
              PVC - advantages
   Cost, flexibility, transparency, resistance to

   DEHP in PVC prolongs shelf-life of red blood
             PVC - disadvantages
   Public health and environmental impacts of
    PVC production, use, and disposal
      Dioxin/furans produced during PVC
       production and incineration
      Leaching of plasticizers, stabilizers (often
       metals) from landfills
      Difficult to recycle
   Potential impacts on direct patient
    health and safety – leaching of DEHP
               PVC and dioxin
   Dioxins and furans generated as by-products of
    manufacture of PVC feedstocks
   Dioxins, furans, HCl formed and released when PVC
    is burned
      Municipal waste incinerators

      Medical waste incinerators

      Landfill fires
   A ―family‖ of chemicals, with similar
    structures, some more toxic than others
   Persistent
      Environment – up to decades

      Humans – half-life 7 years

   Bioaccumulative – concentrations increase as
    it moves up the food chain
    Dioxin – low-dose health effects
   Some seen at pg-ng/kg/day levels of exposure
   Alters levels of many enzymes, growth
       factors, hormones
   Cancer
   Reproductive/Developmental
   Endocrine
   Immune system
Di-ethylhexyl phthalate (DEHP)
                  Phthalate Plasticizer
                  2 million tons/year
                  Ubiquitous exposure
                  General Uses
                     Building materials

                     Clothing

                     Packaging

                     Medical Devices
DEHP in Medical Devices
       Used to make PVC plastic flexible

       20 - 40 % by weight; up to 80% in

       Not bound to the vinyl; readily leaches.

       Leaching increased by lipid-like content
        of fluids, temperature, agitation, storage
    Sources of Medical Exposure to
   Intravenous fluids, medications
   Exchange Transfusions
   Replacement Transfusions
   Extra Corporeal Membrane Oxygenation
   Dialysis
   Surgery; e.g. large exposures during
        cardiopulmonary bypass
   Hyper-alimentation
   Gastric Feeding, NG Tubing
   Artificial Ventilation
DEHP developmental toxicity—
      animal studies
   Developmental/Reproductive Toxicity
     Skeletal, cardiovascular, eye, male reproductive
       tract, neural tube defects
     Intrauterine death and increased post-natal
     Decreased intrauterine and postnatal growth
     Alter sexual differentiation of male
       reproductive system
     Infertility in males and females
    Most Sensitive System:
Immature Male Reproductive Tract
     MEHP is the toxic metabolite
     Mechanism of Action
          testosterone synthesis; interference with
         Leydig cell differentiation with fetal exposures
     Target Tissues
        Sertoli cells, Leydig cells
        Seminiferous tubules, sperm, epididymis, penis,

                    NTP-CERHR-DEHP-00, Oct 2000
                    Moore, 2001 EHP 109:229; Gray LE, NIEHS presentation
    Most Sensitive System:
Immature Male Reproductive Tract
     Impacts on developing male reproductive system
      are at least partially independent of peroxisome
      proliferation, a mechanism which is related to
      cancer causation in rodents.
     Rabbits, mice, rats, guinea pigs, ferrets all show
      toxic impacts. (fetal and newborn primates never
     Therefore, these studies are considered relevant to
Importance of route of exposure;
      species differences
   DEHP converted to MEHP by intestinal
    lipases; less rapid conversion after IV
   DEHP converted to MEHP in all species
    MEHP eliminated largely by glucuronidation
    (primates); further hydrolyzed by humans
    before glucuronidation, by hydrolysis (rodents)
Metabolic age-related differences
 impacting toxicity of DEHP

   Fetus and infant have reduced glucuronidation
    capacity compared to adult
   Infants have higher gastric lipase activity than
    older children/adults
   Children absorb more DEHP from the
    intestinal tract than adults
  Magnitude of Neonatal Exposure
     (General population exposure: 0.003 – 0.030 mg/kg/day)

    Neonatal Exchange Transfusion
       1.8 mg/kg/exch (0.84 – 3.3)
    Replacement Transfusion
       0.3 mg/kg/tx (0.14-0.72)
    ECMO (depending on circuit
     and assumptions)                                  Sjoberg, 1985. Eur J Clin Invest 15:430
                                                       Sjoberg, 1985. Transfusion 25:424
       0.0 – 140 mg/kg DEHP                           Karle, 1997. Crit Care Med 25:696

Levels in children with these exposures exceed the NOAEL in
animal studies
NTP panel – Center for the Evaluation of
   Risks to Human Reproduction

   "serious concern" 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
   "concern" 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.
FDA safety assessment of DEHP
   Considered species differences, pharmaco-
       kinetics, route of exposure
   Developed a ―tolerable intake‖ (TI) for oral
       and parenteral exposure, below which no
    adverse effects expected
   TI based only on developing testes as the
       most sensitive endpoint
    FDA safety assessment (cont’d)

   FDA derived a ―tolerable intake‖ (TI) for
      DEHP via oral and parenteral routes

   TI calculations based on NOAELs and
       LOAELs from numerous animal studies
       of testicular toxicity
    Tolerable intake (TI) for DEHP

   0.6 mg DEHP/kg/day for parenteral exposures
   0.04 mg DEHP/kg/day for oral exposures
   TI/dose ratio identifies procedures or
        treatments that are likely to result in an
        exposure that exceeds the TI
                      adult               neonate

              DEHP dose, TI/dose   DEHP dose   TI/dose
              upper bound
IV:cryst      0.005      120       0.03        20
IV drugs   0.15          4         0.03        20
TPN           0.13       5         2.5         0.2
Enteral                  < 1.0     0.14        0.3
ECMO          3.0        0.2       14          0.04
exchange                           22.6        0.02
    FDA public health notification
          and guidance

   Recommends the use of alternatives to DEHP-
    containing products for those procedures
    where exposures may be excessive
   Recommends reformulation of products to
    decrease/eliminate DEHP exposures
   Recommends labeling of DEHP-containing
            Additional concerns
   Breast milk infusion from non-PVC bag or syringe
        through DEHP-containing tubing
   Simultaneous exposures from multiple sources
      A 4 kg infant in NICU could receive approx

        3 mg DEHP/kg/day for weeks or months
      TI/dose approx 0.05

   Fetal exposures—DEHP/MEHP in cord blood
           Additional concerns
   Background exposures to DEHP approx
    3-30 micrograms/kg/day, up to ¾ of the oral TI
    (diet the largest source in gen’l population)
   Exposure to multiple phthalates, in addn to
    DEHP, that have cumulative impacts
    (CDC’s exposure assessments confirm the
        ubiquity of phthalate exposures.)
           Other effects, DEHP
              (FDA report, annex D)

   DEHP causes platelet aggregation and
    complement activation
   Microemboli during ECMO or cardio-
    pulmonary bypass may be related to DEHP
   Drug loss by binding to surface of PVC tubing
    or bags
        Urinary levels of the DEHP
        metabolite, MEHP, in NICU

          To assess neonatal exposure to DEHP
          containing medical devices encountered in the
          course of ICU care and measure the urinary
          metabolite MEHP.
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)
 Convenience sample of (54) infants
enrolled from two Level III Boston hospital
 Infants were in the NICU at least 3 days
before observation;
 Exposure classification: LOW,
MEDIUM, and HIGH DEHP exposure
classification categories were determined
prior to analysis
       Exposure classification

 LOW exposure: primarily bottle and/or gavage
 MEDIUM exposure: enteral feedings,
  intravenous (IV) hyperalimentation, and/or nasal
  continuous positive airway pressure (CPAP);
 HIGH exposure: umbilical vessel
  catheterization, endotracheal intubation, IV
  hyperalimentation and an indwelling gavage tube
                    Median and IQR of urinary MEHP, by class of
                    DEHP exposure, adjusted for sex and institution.
MEHP ng/ml urine

                            75th percentile

                   160         median

                   100      25th percentile




                        0                     Low      Medium       High
                                              DEHP Exposure Class
     Potential responses to DEHP
   Labeling of DEHP-containing products
   Preferential purchasing policies; alternatives available
    for most products
   Heparin coated PVC tubing reduces platelet
    aggregation and complement activation
   Minimize blood storage time in PVC bags
   Minimize solution agitation and warming
   Follow existing label instructions for drug delivery
    (note that alternative tubing less readily available than
    alternative bags)
     PVC in Hospitals:
Disposable Medical Products
                           Percent of PVC
                          Disposable Products
   Tubing                    43.0%
   Bags                      42.5%
   Gloves                    12.5%
 Source: Schecter, 1996

   Trays for Kits             1.5%
   Catheters                  0.5%
    History of Alternatives to PVC
              1974-’75: EVA TPN bag and polyolefin
                platelet bag -- Baxter

1970s: Polyurethane and silicone umbilical vessel catheters
  and nasogastric tubes

            1980s: Polyolefin/polyester laminate bag for IV
              solutions -- B.Braun

1992: Citrate-softened PVC red blood cell bag --
     Options to DEHP-containing
           Medical Devices
            “DEHP-free” / “Non-DEHP” -- PVC without DEHP
               Alternative plasticizers – citrates, trimellitates,
                adipates – can leach out
               Poor toxicological data on alternatives (some share
                toxicity features of phthalates)

“PVC-free” / “Non-PVC” -- No DEHP, No PVC
    PVC-free alternatives are inherently flexible, no need for
    Materials include: polypropylene, polyethylene, ethylene
     vinyl acetate (EVA), silicone, polyurethane
                     Case Studies
   2002 FDA public health
    notification triggered action
    with ICN staff
   Internal PVC/DEHP audit
    of NICU shelves and                Staff initiated process to
    identified comparable               identify DEHP products in
    alternatives                        NICU, including evaluation
                                        of alternatives
   Switched out virtually all
                                       System-wide switch to non-
    products and replaced with          DEHP products:
    non-DEHP alternatives
                                          umbilical vessel catheters
                                          PICC lines
                                          enteral feeding products
      European Demand - Vienna
         Hospital Association
Glanzing Pediatric and
 Preyer Pediatric Hospitals
    Phase out use of PVC products
     Hospital-Wide – 50% of PVC
     products eliminated

    Glanzing Neonatal Unit – nearly PVC-free
       Almost all invasive PVC products eliminated, including
        nasogastric tubes and umbilical vessel catheters
       Most non-invasive PVC products eliminated, including
                        Enteral Feeding
               VIASYS Healthcare (formerly CORPAK)
              PVC-free bags: nylon/EVA/polypropylene
              PVC-free tubes (gastrostomy, nasoenteric, PEG):
               silicone, polyurethane
                                                                      VIASYS: Farrell valve

                        Tyco (Kendall) Healthcare
                                DEHP-free enteral feeding sets
 Kendall: DEHP-free
 Kangaroo Set                   PVC-free tubes: silicone,
                                                                         Arrow Int’l:
                                                                         silicone feeding

                          Arrow International (formerly Klein Baker)
                     PVC-free feeding tubes for neonates: silicone

Other Manufacturers: Bard, Ross, Utah
  Medical, Vygon, Zevex
Total Parenteral Nutrition (TPN)

PVC-free TPN bags: Ethylene Vinyl Acetate
   Baxter Healthcare

   Baxa Corp.

                            Baxter Compounding System

     Baxa Corp.
        IV Products                          Admin Sets

          IV Containers
                                      -- Medex, Inc.
PVC-free:                             -- Natvar
-- B Braun (PP/PE/Polyester)          (polyurethane)


           B Braun
EXCEL® and PAB® IV Containers
 Innovative PVC-Free and DEHP-Free   --many manufacturers
plastic IV containers
                  Market Trends
DEHP-free Products Widely
     Most vendors now have clearly labeled
      DEHP-free product lines
     Especially for tubing applications
   PVC-free                                    Hospira

          Alternative plastics to PVC        Hospira webpage …
           are the material of choice for     Nutrimix® Dual
                                              Chamber Flexible
                                              Container > TPN:
          Better performance: more           ...
           compatible with a wider range      …
           of drugs, less concern with         Non-DEHP
           leaching                           containers and sets
Performance of PVC-free Alternatives
          PVC-free plastics inherently flexible – no
          Chlorine-free w/exception of neoprene gloves
          PVC-free plastics compatible with broader range of
                   Bags: cost-competitive due to
                   Tubing: can cost more, but may have longer
                    use life
                   Gloves: cost-competitive at large volume

              Clear, flexible, often steam sterilizable
 Environmental Spectrum of Plastics

                     LIFE CYCLE HAZARDS

          Polyurethane EVA         Polyethylene    Bio-based
          Polycarbonate Silicone   Polypropylene   plastics

AVOID                                                 PREFER

Sustainable Hospitals Project

                  Health Care Without Harm