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PVC and DEHP in medical
devices:
problems and solutions
Sarah Janssen, MD, PhD, MPH
SF Bay Area Physicians for Social Responsibility
Science Fellow – Natural Resources Defense
Council
August 2006
Acknowledgements
This document reflects the work of many people within
Health Care Without Harm and SF Bay Area PSR.
Special thanks to:
Ted Schettler, MD, MPH – Science and Environmental
Health Network
Mark Rossi, PhD – Clean Production Action
Julie Silas, JD – SF Bay Area Physicians for Social
Responsibility
Valerie Briscoe, MSN, NNP, CNS- John Muir Medical
Center
Polyvinyl chloride (PVC)
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 coverings
Vinyl chloride polymer
PVC
Produced with fillers, stabilizers, pigments,
plasticizers, lubricants, anti-oxidants, flame
retardants (dependent on application)
Plasticizers – phthalates; di-ethylhexyl
phthalate (DEHP) used in medical devices
DEHP
PVC - advantages
Cost, flexibility, transparency, resistance to
breakage
DEHP in PVC prolongs shelf-life of red
blood cells
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 dioxins
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
Dioxin
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, and 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
tubing.
Not bound to the vinyl; readily
leaches.
Leaching increased by lipid-like
content of fluids, temperature,
agitation, storage time.
Sources of Medical Exposure to
DEHP
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
o Skeletal, cardiovascular, eye, male reproductive
tract, neural tube defects
o Intrauterine death and increased post-natal
death
o Decreased intrauterine and postnatal growth
o Infertility in males and females
o Alter sexual differentiation of male
reproductive system
Most Sensitive System:
Immature Male Reproductive Tract
Mono (2-ethylhexyl) phthalate (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,
prostate
NTP-CERHR-DEHP-00, Oct 2000
Moore, 2001 EHP 109:229; Gray LE, NIEHS presentation
Relevance to Humans
Rabbits, mice, rats, guinea pigs, ferrets all
show toxic impacts. (Fetal and newborn
primates never studied.)
Therefore, these studies are considered
relevant to humans
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
infants.
“concern” that DEHP exposure can adversely
affect reproductive development in infants less
than 1 year old because of their greater
susceptibility and uncertainties regarding
exposure. NTP-CERHR Expert Panel Update on the Reproductive
and Developmental Toxicity of DEHP, November 2005
Importance of route of exposure;
species differences
DEHP converted to MEHP by intestinal
lipases; less rapid conversion after IV
administration
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
Human fetus and infant have reduced
glucuronidation capacity compared to
adults
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) DEHP
Replacement Transfusion
0.3 mg/kg/tx (0.14-0.72) DEHP
ECMO (depending on circuit and
assumptions)
0.0 – 140 mg/kg DEHP
Levels in children with these exposures exceed the
NOAEL in animal studies
Sjoberg, 1985. Eur J Clin Invest 15:430
Sjoberg, 1985. Transfusion 25:424
Karle, 1997. Crit Care Med 25:696
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 of DEHP, September 2001
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.
A TI/dose ratio < 1 signifies the dose of DEHP
received during a treatment exceeds a safe level
Adult Neonate
DEHP dose, TI/dose DEHP dose TI/dose
mg/kg/day,
Procedure upper bound
IV: cryst 0.005 120 0.03 20
IV drugs 0.15 4 0.03 20
w/vehicles
TPN (lipid) 0.13 5 2.5 0.2
Enteral < 1.0 0.14 0.3
nutrition
ECMO 3.0 0.2 14 0.04
exchange 22.6 0.02
transfusion
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 products
FDA Public Health Notification: PVC Devices Containing the
Plasticizer DEHP, July 2002.
Additional concerns
Breast milk infusion from 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 general population)
Exposure to multiple phthalates, in addition to
DEHP, that have cumulative impacts
(CDC’s exposure assessments confirm the
ubiquity of phthalate exposures.)
www.cdc.gov/exposurereport
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
infants
Assessed neonatal exposure to DEHP containing
medical devices encountered in the course of ICU care
and measured the urinary metabolite MEHP.
“Use of di(2-ethylhexyl) phthalate-containing medical products and urinary levels of
mono(2-ethylhexyl) phthalate in neonatal intensive care unit infants.” Green R, Hauser R,
Calafat AM, et al. Environ Health Perspect. 2005 Sep;113(9):1222-5.
Harvard NICU Exposure
Study: Methods
Samples from (54) infants enrolled from two
Level III Boston hospital nurseries;
Infants were in the NICU at least 3
days before measurement of urine levels of
MEHP
Exposure classification: LOW, MEDIUM,
and HIGH DEHP exposure classification
categories were determined prior to analysis
Exposure classification
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
Median and IQR of urinary MEHP, by class of DEHP
exposure, adjusted for sex and institution
200
MEHP ng/ml urine
75th percentile
180
160 median
140
120
100 25th percentile
80
60
40
20
0 Low Medium High
DEHP Exposure Class
Potential responses to DEHP
concerns
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)
Resources
Health Care Without Harm
www.noharm.org
Sustainable Hospitals Project
www.sustainablehospitals.org
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