PVC and DEHP in PVC and DEHP in medical devices: medical devices:
problems and problems and solutionssolutions
Ted Schettler MD, MPHTed Schettler MD, MPH
Science and Environmental Health Science and Environmental Health NetworkNetwork
and and
Boston Medical CenterBoston Medical Center
October 2005
Polyvinyl chloride (PVC)Polyvinyl chloride (PVC)
Vinyl chloride polymerVinyl chloride polymer Most widely used plastic in medical products – Most widely used plastic in medical products –
27% of all plastic used in 199627% of all plastic used in 1996 445 million pounds in bags, tubing, gloves, 445 million pounds in bags, tubing, gloves,
trays, catheters, etc.; also in non-medical trays, catheters, etc.; also in non-medical supplies, flooring, pipes, and wall supplies, flooring, pipes, and wall
coveringscoverings
PVCPVC
Produced with fillers, stabilizers, pigments, Produced with fillers, stabilizers, pigments, plasticizers, lubricants, anti-oxidants, flame plasticizers, lubricants, anti-oxidants, flame retardants (dependent on application)retardants (dependent on application)
Plasticizers – phthalates; di-ethylhexyl Plasticizers – phthalates; di-ethylhexyl phthalate (DEHP) used in medical devicesphthalate (DEHP) used in medical devices
PVC - advantagesPVC - advantages
Cost, flexibility, transparency, resistance to Cost, flexibility, transparency, resistance to breakagebreakage
DEHP in PVC prolongs shelf-life of red blood DEHP in PVC prolongs shelf-life of red blood cells cells
PVC - disadvantagesPVC - disadvantages
Public health and environmental impacts of Public health and environmental impacts of PVC production, use, and disposalPVC production, use, and disposal Dioxin/furans produced during PVC Dioxin/furans produced during PVC
production and incineration production and incineration Leaching of plasticizers, stabilizers (often Leaching of plasticizers, stabilizers (often
metals) from landfillsmetals) from landfills Difficult to recycleDifficult to recycle
Potential impacts on direct patient Potential impacts on direct patient health and safety – leaching of DEHPhealth and safety – leaching of DEHP
PVC and dioxinPVC and dioxin
Dioxins and furans generated as by-products of Dioxins and furans generated as by-products of manufacture of PVC feedstocksmanufacture of PVC feedstocks
Dioxins, furans, HCl formed and released when PVC Dioxins, furans, HCl formed and released when PVC is burned is burned Municipal waste incinerators Municipal waste incinerators Medical waste incineratorsMedical waste incinerators Landfill firesLandfill fires
Dioxin Dioxin
A “family” of chemicals, with similar A “family” of chemicals, with similar structures, some more toxic than othersstructures, some more toxic than others
Persistent Persistent Environment – up to decadesEnvironment – up to decades Humans – half-life 7 yearsHumans – half-life 7 years
Bioaccumulative – concentrations increase as Bioaccumulative – concentrations increase as it moves up the food chainit moves up the food chain
Dioxin – low-dose health Dioxin – low-dose health effectseffects
Some seen at pg-ng/kg/day levels of Some seen at pg-ng/kg/day levels of exposureexposure
Alters levels of many enzymes, growth Alters levels of many enzymes, growth factors, hormonesfactors, hormones
CancerCancer Reproductive/DevelopmentalReproductive/Developmental EndocrineEndocrine Immune systemImmune system
Di-ethylhexyl phthalate Di-ethylhexyl phthalate (DEHP)(DEHP)
Phthalate PlasticizerPhthalate Plasticizer 2 million tons/year2 million tons/year Ubiquitous exposureUbiquitous exposure General UsesGeneral Uses
Building materialsBuilding materials ClothingClothing PackagingPackaging Medical DevicesMedical Devices
DEHP in Medical DEHP in Medical DevicesDevices
Used to make PVC plastic flexibleUsed to make PVC plastic flexible
20 - 40 % by weight; up to 80% in tubing.20 - 40 % by weight; up to 80% in tubing.
Not bound to the vinyl; readily leaches.Not bound to the vinyl; readily leaches.
Leaching increased by lipid-like content of Leaching increased by lipid-like content of fluids, temperature, agitation, storage time.fluids, temperature, agitation, storage time.
Sources of Medical Sources of Medical Exposure to DEHPExposure to DEHP
Intravenous fluids, medications Intravenous fluids, medications Exchange TransfusionsExchange Transfusions Replacement TransfusionsReplacement Transfusions Extra Corporeal Membrane OxygenationExtra Corporeal Membrane Oxygenation DialysisDialysis Surgery; e.g. large exposures during Surgery; e.g. large exposures during
cardiopulmonary bypasscardiopulmonary bypass Hyper-alimentationHyper-alimentation Gastric Feeding, NG TubingGastric Feeding, NG Tubing Artificial VentilationArtificial Ventilation
DEHP developmental DEHP developmental toxicity—animal studies toxicity—animal studies
Developmental/Reproductive ToxicityDevelopmental/Reproductive Toxicity Skeletal, cardiovascular, eye, male reproductive Skeletal, cardiovascular, eye, male reproductive
tract, neural tube defects tract, neural tube defects Intrauterine death and increased post-natal Intrauterine death and increased post-natal deathdeath Decreased intrauterine and postnatal growthDecreased intrauterine and postnatal growth Alter sexual differentiation of male Alter sexual differentiation of male reproductive reproductive
systemsystem Infertility in males and females Infertility in males and females
Most Sensitive System:Most Sensitive System:Immature Male Immature Male
Reproductive TractReproductive Tract MEHP is the toxic metaboliteMEHP is the toxic metabolite Mechanism of ActionMechanism of Action
testosterone synthesis; interference with testosterone synthesis; interference with Leydig cell differentiation with fetal exposuresLeydig cell differentiation with fetal exposures
Target TissuesTarget Tissues Sertoli cells, Leydig cells Sertoli cells, Leydig cells Seminiferous tubules, sperm, epididymis, penis, Seminiferous tubules, sperm, epididymis, penis,
prostate prostate
NTP-CERHR-DEHP-00, Oct 2000Moore, 2001 EHP 109:229; Gray LE, NIEHS presentation
Most Sensitive System:Most Sensitive System:Immature Male Immature Male
Reproductive TractReproductive Tract Impacts on developing male reproductive system Impacts on developing male reproductive system
are at least partially independent of peroxisome are at least partially independent of peroxisome proliferation, a mechanism which is related to proliferation, a mechanism which is related to cancer causation in rodents. cancer causation in rodents.
Rabbits, mice, rats, guinea pigs, ferrets all show Rabbits, mice, rats, guinea pigs, ferrets all show toxic impacts. (fetal and newborn primates never toxic impacts. (fetal and newborn primates never studied)studied)
Therefore, these studies are considered relevant to Therefore, these studies are considered relevant to humanshumans
Importance of route of Importance of route of exposure; species exposure; species
differencesdifferences DEHP converted to MEHP by intestinal DEHP converted to MEHP by intestinal
lipases; less rapid conversion after IV lipases; less rapid conversion after IV administration administration
DEHP converted to MEHP in all speciesDEHP converted to MEHP in all species MEHP eliminated largely by glucuronidation MEHP eliminated largely by glucuronidation
(primates); further hydrolyzed by humans (primates); further hydrolyzed by humans before glucuronidation, by hydrolysis before glucuronidation, by hydrolysis (rodents)(rodents)
Metabolic age-related Metabolic age-related differences impacting differences impacting
toxicity of DEHPtoxicity of DEHP
Fetus and infant have reduced glucuronidation Fetus and infant have reduced glucuronidation capacity compared to adultcapacity compared to adult
Infants have higher gastric lipase activity than Infants have higher gastric lipase activity than older children/adultsolder children/adults
Children absorb more DEHP from the Children absorb more DEHP from the intestinal tract than adultsintestinal tract than adults
Magnitude of Neonatal Magnitude of Neonatal ExposureExposure
(General population exposure: 0.003 – 0.030 (General population exposure: 0.003 – 0.030 mg/kg/day)mg/kg/day)
Neonatal Exchange Transfusion Neonatal Exchange Transfusion
1.8 mg/kg/exch (0.84 – 3.3) 1.8 mg/kg/exch (0.84 – 3.3) DEHPDEHP
Replacement Transfusion Replacement Transfusion 0.3 mg/kg/tx (0.14-0.72) 0.3 mg/kg/tx (0.14-0.72)
DEHPDEHP ECMO (depending on circuit ECMO (depending on circuit
and assumptions) and assumptions) 0.0 – 140 mg/kg DEHP 0.0 – 140 mg/kg DEHP
Sjoberg, 1985. Eur J Clin Invest 15:430Sjoberg, 1985. Transfusion 25:424Karle, 1997. Crit Care Med 25:696
Levels in children with these exposures exceed Levels in children with these exposures exceed the NOAEL in animal studiesthe NOAEL in animal studies
NTP panel – Center for the NTP panel – Center for the Evaluation of Risks to Human Evaluation of Risks to Human
ReproductionReproduction "serious concern" for the possibility of adverse effects "serious concern" for the possibility of adverse effects
on the developing reproductive tract of male infants on the developing reproductive tract of male infants exposed to very high levels of DEHP that might be exposed to very high levels of DEHP that might be associated with intensive medicalassociated with intensive medicalprocedures such as those used in critically ill infants. procedures such as those used in critically ill infants.
"concern" that, if infants and toddlers are exposed to "concern" that, if infants and toddlers are exposed to levels of DEHP substantially higher than adults, levels of DEHP substantially higher than adults, adverse effects might occur in the developing male adverse effects might occur in the developing male reproductive tract. reproductive tract.
FDA safety assessment of FDA safety assessment of DEHPDEHP
Considered species differences, pharmaco-Considered species differences, pharmaco-kinetics, route of exposurekinetics, route of exposure
Developed a “tolerable intake” (TI) for oral Developed a “tolerable intake” (TI) for oral and parenteral exposure, below which and parenteral exposure, below which no no adverse effects expected adverse effects expected
TI based only on developing testes as the TI based only on developing testes as the most sensitive endpointmost sensitive endpoint
FDA safety assessment FDA safety assessment (cont’d)(cont’d)
FDA derived a “tolerable intake” (TI) for FDA derived a “tolerable intake” (TI) for DEHP via oral and parenteral routesDEHP via oral and parenteral routes
TI calculations based on NOAELs and TI calculations based on NOAELs and LOAELs from numerous animal studies LOAELs from numerous animal studies of of testicular toxicitytesticular toxicity
Tolerable intake (TI) for Tolerable intake (TI) for DEHPDEHP
0.6 mg DEHP/kg/day for parenteral 0.6 mg DEHP/kg/day for parenteral exposuresexposures
0.04 mg DEHP/kg/day for oral exposures0.04 mg DEHP/kg/day for oral exposures TI/dose ratio identifies procedures or TI/dose ratio identifies procedures or
treatments that are likely to result in an treatments that are likely to result in an exposure that exceeds the TIexposure that exceeds the TI
DEHP dose,DEHP dose, mg/kg/day,mg/kg/day,
upper boundupper bound
TI/doseTI/dose DEHP doseDEHP dose TI/doseTI/dose
IV:crystIV:cryst 0.0050.005 120120 0.030.03 2020
IV drugsIV drugs
w/vehiclesw/vehicles0.150.15 44 0.030.03 2020
TPN TPN (lipid)(lipid)
0.130.13 55 2.52.5 0.20.2
Enteral Enteral nutritionnutrition
< 1.0< 1.0 0.140.14 0.30.3
ECMOECMO 3.03.0 0.20.2 1414 0.040.04
exchange exchange transfusiontransfusion
22.622.6 0.020.02
adult neonate
FDA public health FDA public health notification and guidancenotification and guidance
Recommends the use of alternatives to DEHP-Recommends the use of alternatives to DEHP-containing products for those procedures containing products for those procedures where exposures may be excessivewhere exposures may be excessive
Recommends reformulation of products to Recommends reformulation of products to decrease/eliminate DEHP exposures decrease/eliminate DEHP exposures
Recommends labeling of DEHP-containing Recommends labeling of DEHP-containing productsproducts
Additional concernsAdditional concerns
Breast milk infusionBreast milk infusion from non-PVC bag or syringe from non-PVC bag or syringe through DEHP-containing tubingthrough DEHP-containing tubing
Simultaneous exposuresSimultaneous exposures from multiple sources from multiple sources A 4 kg infant in NICU could receive approx A 4 kg infant in NICU could receive approx
3 mg DEHP/kg/day for weeks or months3 mg DEHP/kg/day for weeks or months TI/dose approx TI/dose approx 0.050.05
Fetal exposures—DEHP/MEHP in cord bloodFetal exposures—DEHP/MEHP in cord blood
Additional concernsAdditional concerns
Background exposures to DEHP approx Background exposures to DEHP approx
3-30 micrograms/kg/day, up to ¾ of the oral 3-30 micrograms/kg/day, up to ¾ of the oral TI (diet the largest source in gen’l population)TI (diet the largest source in gen’l population)
Exposure to multiple phthalates, in addn to Exposure to multiple phthalates, in addn to DEHP, that have cumulative impactsDEHP, that have cumulative impacts
(CDC’s exposure assessments confirm the (CDC’s exposure assessments confirm the ubiquity of phthalate exposures.)ubiquity of phthalate exposures.)
www.cdc.gov/exposurereportwww.cdc.gov/exposurereport
Other effects, DEHP Other effects, DEHP (FDA report, annex D)(FDA report, annex D)
DEHP causes platelet aggregation and DEHP causes platelet aggregation and complement activationcomplement activation
Microemboli during ECMO or cardio-Microemboli during ECMO or cardio-pulmonary bypass may be related to DEHPpulmonary bypass may be related to DEHP
Drug loss by binding to surface of PVC tubing Drug loss by binding to surface of PVC tubing or bagsor bags
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.
Convenience sample of (54) infants enrolled from two Level III Boston hospital nurseries;
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
Methods
LOW exposure: primarily bottle and/or gavage feedings;
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
Exposure classification
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
ME
HP
ng/
ml u
rine
median
75th percentile
25th percentile
DEHP Exposure Class
Potential responses to Potential responses to DEHP concerns DEHP concerns
Labeling of DEHP-containing productsLabeling of DEHP-containing products Preferential purchasing policies; alternatives available Preferential purchasing policies; alternatives available
for most productsfor most products Heparin coated PVC tubing reduces platelet Heparin coated PVC tubing reduces platelet
aggregation and complement activationaggregation and complement activation Minimize blood storage time in PVC bagsMinimize blood storage time in PVC bags Minimize solution agitation and warmingMinimize solution agitation and warming Follow existing label instructions for drug delivery Follow existing label instructions for drug delivery
(note that alternative tubing less readily available (note that alternative tubing less readily available than alternative bags)than alternative bags)
PVC in Hospitals: PVC in Hospitals: Disposable Medical Disposable Medical
ProductsProducts Percent of PVCPercent of PVC Disposable ProductsDisposable Products
Tubing Tubing 43.0%43.0%
Bags Bags 42.5%42.5%
Gloves Gloves 12.5%12.5%
Trays for KitsTrays for Kits 1.5% 1.5%
Catheters Catheters 0.5% 0.5%
Source: Schecter, 1996
History of Alternatives History of Alternatives to PVCto PVC
1974-’75: 1974-’75: EVAEVA TPN bag and TPN bag and polyolefin polyolefin platelet bag -- Baxterplatelet bag -- Baxter
1992: 1992: Citrate-softened PVCCitrate-softened PVC red red blood cell bag -- Baxterblood cell bag -- Baxter
1980s: 1980s: Polyolefin/polyesterPolyolefin/polyester laminate laminate bag for IV solutions -- B.Braunbag for IV solutions -- B.Braun
1970s: 1970s: PolyurethanePolyurethane and s and siliconeilicone umbilical umbilical vessel catheters and nasogastric tubesvessel catheters and nasogastric tubes
Options to DEHP-Options to DEHP-containing Medical containing Medical
DevicesDevices““DEHP-free” / “Non-DEHP” -- PVC without DEHPDEHP-free” / “Non-DEHP” -- PVC without DEHP
Alternative plasticizers – citrates, trimellitates, Alternative plasticizers – citrates, trimellitates, adipates – can leach outadipates – can leach out
Poor toxicological data on alternatives (some Poor toxicological data on alternatives (some share toxicity features of phthalates)share toxicity features of phthalates)
““PVC-free” / “Non-PVC” -- No DEHP, No PVCPVC-free” / “Non-PVC” -- No DEHP, No PVC PVC-free alternatives are inherently flexible, no need for PVC-free alternatives are inherently flexible, no need for
plasticizersplasticizers Materials include: polypropylene, polyethylene, ethylene Materials include: polypropylene, polyethylene, ethylene
vinyl acetate (EVA), silicone, polyurethanevinyl acetate (EVA), silicone, polyurethane
Staff initiated process to Staff initiated process to identify DEHP products in identify DEHP products in NICU, including evaluation NICU, including evaluation of alternativesof alternatives
System-wide switch to non-System-wide switch to non-DEHP products: DEHP products: umbilical vessel catheters umbilical vessel catheters PICC linesPICC lines enteral feeding productsenteral feeding products
2002 FDA public health 2002 FDA public health notification triggered action notification triggered action with ICN staffwith ICN staff
Internal PVC/DEHP audit Internal PVC/DEHP audit of NICU shelves and of NICU shelves and identified comparable identified comparable alternativesalternatives
Switched out virtually all Switched out virtually all products and replaced with products and replaced with non-DEHP alternativesnon-DEHP alternatives
Case Case StudiesStudies
European Demand - European Demand - Vienna Hospital Vienna Hospital
AssociationAssociationGlanzing Pediatric and Glanzing Pediatric and
Preyer Pediatric HospitalsPreyer Pediatric Hospitals
Glanzing Neonatal Unit – nearly PVC-freeGlanzing Neonatal Unit – nearly PVC-free Almost all invasive PVC products eliminated, including Almost all invasive PVC products eliminated, including
nasogastric tubes and umbilical vessel cathetersnasogastric tubes and umbilical vessel catheters Most non-invasive PVC products eliminated, including Most non-invasive PVC products eliminated, including
IVIV
Phase out use of PVC products Phase out use of PVC products Hospital-Wide – 50% of PVC Hospital-Wide – 50% of PVC products eliminatedproducts eliminated
Enteral Enteral FeedingFeeding
VIASYS: Farrell valve
Kendall: DEHP-free Kangaroo Set
Arrow Int’l: silicone feeding tube
Arrow InternationalArrow International (formerly Klein Baker)(formerly Klein Baker) PVC-free feeding tubes for neonates: siliconePVC-free feeding tubes for neonates: silicone
Tyco (Kendall) HealthcareTyco (Kendall) Healthcare DEHP-free enteral feeding setsDEHP-free enteral feeding sets PVC-free tubes: silicone, PVC-free tubes: silicone,
polyurethane polyurethane
VIASYS HealthcareVIASYS Healthcare (formerly CORPAK (formerly CORPAK))
PVC-free bags: nylon/EVA/polypropylenePVC-free bags: nylon/EVA/polypropylene PVC-free tubes (gastrostomy, nasoenteric, PEG): PVC-free tubes (gastrostomy, nasoenteric, PEG):
silicone, polyurethanesilicone, polyurethane
Other Manufacturers: Bard, Ross, Utah Other Manufacturers: Bard, Ross, Utah Medical, Vygon, ZevexMedical, Vygon, Zevex
Total Parenteral Total Parenteral Nutrition (TPN)Nutrition (TPN)
PVC-freePVC-free TPN bags: Ethylene Vinyl Acetate TPN bags: Ethylene Vinyl Acetate Baxter HealthcareBaxter Healthcare Baxa Corp.Baxa Corp.
Baxa Corp.
Baxter Compounding System
IV IV ProductsProducts
IV ContainersIV Containers
EXCEL® and PAB® IV EXCEL® and PAB® IV ContainersContainers Innovative PVC-Free and Innovative PVC-Free and DEHP-Free plastic IV DEHP-Free plastic IV containers containers ……
DEHP-free:
--many manufacturers
Medex
Admin Sets
PVC-free:
-- Medex, Inc.
(polyethylene)
-- Natvar (polyurethane)
PVC-free:PVC-free: -- B Braun (PP/PE/Polyester)-- B Braun (PP/PE/Polyester)
B Braun
Market TrendsMarket Trends
PVC-freePVC-free Alternative plastics to PVC Alternative plastics to PVC
are the material of choice for are the material of choice for bagsbags
Better performance: more Better performance: more compatible with a wider range compatible with a wider range of drugs, less concern with of drugs, less concern with leachingleaching
Hospira webpage … Nutrimix® Dual Chamber Flexible Container > TPN:...… Non-DEHP containers and sets available
DEHP-freeDEHP-free Products Widely Products Widely AvailableAvailable Most vendors now have clearly labeled Most vendors now have clearly labeled
DEHP-free product linesDEHP-free product lines Especially for tubing applicationsEspecially for tubing applications
Hospira
Performance of PVC-free Performance of PVC-free AlternativesAlternatives
SafetySafety PVC-free plastics PVC-free plastics inherently flexibleinherently flexible – no – no
plasticizersplasticizers Chlorine-freeChlorine-free w/exception of neoprene gloves w/exception of neoprene gloves PVC-free plastics PVC-free plastics compatible with broader range of compatible with broader range of
drugsdrugs
PerformancePerformance Clear, flexible, often steam sterilizableClear, flexible, often steam sterilizable
CostsCosts BagsBags: cost-competitive due to : cost-competitive due to
“downgauging”“downgauging” TubingTubing: can cost more, but may have longer : can cost more, but may have longer
use lifeuse life GlovesGloves: cost-competitive at large volume: cost-competitive at large volume
Environmental Spectrum of Environmental Spectrum of PlasticsPlastics
PVC PolyethylenePolypropylene
AVOID
LIFE CYCLE HAZARDS
PolyurethanePolycarbonate
EVASilicone
Bio-based plastics
PREFER
ResourceResourcess
Sustainable Hospitals ProjectSustainable Hospitals Projectwww.sustainablehospitals.orgwww.sustainablehospitals.org
Health Care Without HarmHealth Care Without Harm
www.noharm.orgwww.noharm.org
