Endocrine disruptors in the healthcare sector

Health Care Without Harm Europe
Endocrine Disruptors in the Health Care
Sector
Wednesday 24th September
15:30-16:30 CEST

What are EDCs
&
How does exposure affect human
health?
R. Thomas Zoeller
Biology Department
College of Natural Sciences

What is an Endocrine Disrupting
Chemical?

Chemical?
 “An ED is an exogenous chemical or mixture of
chemicals that can interfere with any aspect of
hormone action” – Endocrine Society
 “interfere” means to trigger or block hormone action
 “any aspect” means to interfere with the hormone
receptor or with the delivery of the hormone to the
receptor
 “hormone action” means “what the hormone does”

Chemical?
 To test if a chemical interferes with hormone action,
you have to know what the hormone does.
 The problem is that hormones do different things in
different “places” at different times!
 So EDCs may interfere with a hormone’s action
selectively….
 Could be receptor isoform specific
 Could be “metabolism” specific
 Almost certain is differentially sensitive

Example:
PCBs, Brain Development and Thyroid
Hormone Action

Schantz SL, Widholm
JJ, Rice DC. Environ
Health Perspect. 2003
Mar;111(3):357-576.
PCB exposure
is associated
with cognitive
deficits

Thyroid hormone deficiency produces
effects on cognitive function that are
similar to that of PCB exposure
Therefore, could PCB exposure be
producing neurocognitive deficits by
reducing thyroid hormone levels?

PCB exposure in animals
almost uniformly causes a
reduction in serum total and
free (not shown) T4.

If PCB – induced reduction in serum T4
is predictive of “downstream” effects,
then PCB exposure should reduce the
expression of thyroid hormone
responsive genes in the developing
brain.

25
30
35
40
45
50
55
60
RC3 mRNA in Dentate
Gyrus (Density)
* *
RC3
Pseudocolor image of
Autoradiogram following in situ
hybridization for RC3 mRNA
Cx
DG
0 mg/kg 1 mg/kg 4 mg/kg 8 mg/kg
A1254 Dose
PCB effects on serum T4 were not
consistent with PCB effect on TH-
regulated genes

PCBs in in vitro and in vivo studies
Non-ortho PCB congener
Coplanar
Dioxin-like
Mono-ortho PCB congener
Non-coplanar
Di-ortho PCB congener
Non-coplanar
Gauger, KJ. et al, (2007); Envir. Health Pers. 115(11), 1623-1630
Are there TR agonists among PCB
congeners?

Gauger, KJ. et al, (2007); Envir. Health Pers. 115(11), 1623-1630
Only the right mixture activated
the TR

4. Hypothesis
CYP1A1
TH target genes
TRTR
TRE
AHR
XRE
ARNT
CYP1A1
coplanar
PCB 126
non-coplanar
PCB 105
PCB 138
PCB 153
PCB 118

Testing the hypothesis in humans
 If environmental chemicals (e.g., PCBs) can be
“activated” by CYP1A1 to form TR agonists which then
drive (±) TH-response genes independent of serum TH,
then:
 CYP1A1 expression should be correlated with the
expression of TH response genes?

Conclusions
 Animal studies demonstrate that some EDCs can
interfere with thyroid hormone action in tissues (e.g.,
developing brain) in a manner that is not reflected in
serum thyroid hormone levels.
 Human studies identify associations between toxicant
exposures and measures of cognitive function (as well as
other outcomes), but relationships with measures of
thyroid function have been inconsistent.
 Capturing indices of hormone action in tissues will be
essential to translate experimental studies to the
human population.

• Ingestion: food, dust, water
• Inhalation: gases, air particles
• Dermal absorption: personal care, dust
• Breast Milk
“We live in a chemical soup”
Is there summation or synergy?

Most Vulnerable Time for Exposure
All of the chemicals highlighted
before are found in cord blood at
birth. But, each baby has a total of
about 100 chemicals “on board”.
One study.
10 cord samples.
287 commercial chemicals,
pesticides, and pollutants.

Endocrine Disruptors in the Health Care Sector
Wednesday 24th September
15:30-16:30 CEST

Children are a product of their
environment
Gavin W. ten Tusscher, M.D., Ph.D., paediatrician
Department of Paediatrics and Neonatology
Westfriesgasthuis, Hoorn, Netherlands

Webinar,
24/09/2014
Gavin ten Tusscher 25
Overview
– What’s the problem?
– What’s the danger?
– What’s the solution?

Webinar,
24/09/2014
Health care: a source, but not the
primary source, of exposure to
toxics
Fetus in
Womb /
Child at
Home
Infant/Child
in Hospital
Child at
Home
Toxic Chemicals

Webinar,
24/09/2014
Sources of exposure to
toxic chemicals in hospitals
Mother
-- Breast
feeding
Patient —
Infant/Child
Medical Devices
-- IV administration
-- Enteral nutrition
-- Direct contact
-- Inhalation
-- Dermal
Hospital
Environment
-- Inhalation
(air quality)
-- Water
-- Food
-- Dermal

Webinar,
24/09/2014
Most at risk
– Foetus, prematurely born, small for gestational age,
seriously ill child
– Higher fat : water ratio but often less total body fat, long
periods of exposure (in hospital)
– Often life-long accumulative exposure
– Organs (brain) still developing
– Less effective blood-brain and blood-testis barrier

Webinar,
24/09/2014
DEHP
– Softeners in plastic (PVC)
– Known for 30 years that it leaks out of medical devices
– Shown to leak from:
• nasogastric tubes, respiratory tubes, endotracheal tubes, umbilical
catheters, PVC blood bags, transfusion tubing systems,
haemodialysis systems, cardiopulmonary bypass, continuous
peritoneal dialysis, ECMO, infusion tubing
– Suspected of teratogenicity and endocrine disruption

Webinar,
24/09/2014
DEHP and
children
– highly lipophilic (over placenta, in breast milk)
– pancreatic lipase most important detoxifier
– much lower levels of pancreatic lipase in neonates
– greater absorption in children
– vulnerable developmental windows

Webinar,
24/09/2014
NICU exposure
to DEHP
– 6 premature infants expected to have i.v. infusion for > 2
weeks included
– 7 urine samples per infant
– DEHP metabolites (mEHHP, mEOHP, mEHP) measured
by CDC
– 41 samples (1 sample no urine extractable)
– 33 samples positive for all 3 metabolites
Calafat et al. Pediatrics 2004;113(5):e429-3

Webinar,
24/09/2014
Cohort

Webinar,
24/09/2014
Results

Webinar,
24/09/2014
Discussion
– geometric mean mEHP (100 ng/mL) prems
• significantly higher than 19 toddlers 12 – 18 months (4.6 ng/mL)
• 26 fold higher than US median for children 6 – 11 yrs
– mEHHP and mEOHP 1-2 order of magnitude higher than
US population (62 adults and children)
– no correlation with specific procedure, GA, birth weight

Webinar,
24/09/2014
In utero exposure
vs gestational age
– Cord blood samples obtained in 84 consecutive newborns
(82 singletons, 2 twins)
– General practice hospital
– 39 males, 45 females
– 11 preterm, 3 VSGA, 4 SGA
– No in vitro fertilisation
– Sampling with glass devices
Latini et al. Environ Health Perspect 2003;111(14):1783-5

Webinar,
24/09/2014
Results
– Logistic regression:
• Significant inverse relation mEHP & GA at birth (38.16 ± 2.34 vs
39.35 ± 1.35 wks)
• OR 1.5 (CI 1.013-2.21) presence/absence mEHP

Webinar,
24/09/2014
Exposure
– Endotracheal tubes show 6 – 12 % loss of DEHP during
use  most probably into the lungs
Latini & Avery. Acta Paediatr 1999;88(10):1174-75
– Priming of ECMO circuits with saline increased circuit
degradation Karle et al. Crit Care Med 1997;25(4):696-703
– DEHP negative infants showed 6.1 to 21.6 mcg/mL after a
single exchange transfusion
– DEHP found in lung tissue in preterms after mechanical
ventilation Roth et al. Eur J Pediatr 1988;147(1):42-6

Webinar,
24/09/2014
DEHP
– “normal” daily exposure 3-30 mcg/kg BW/day
– NICU enteral nutrition 40-140 mcg/kg BW/day
– NICU parental nutrition up to 2500 mcg/kg BW/day !!
– Total daily intake in all children (< 19 yrs) > adults

Webinar,
24/09/2014
Bear in mind
– DEHP toxicity shown in animal studies (long term toxicity &
tissue deposition)
– DEHP exposure is life-long, ubiquitous environmental
contaminant
– No longer in toys for children < 3 yrs (EU 1999/815/EG)
– US FDA consider NICU patients at particular risk

Webinar,
24/09/2014
American Medical
Association
H-135.945 Encouraging Alternatives to PVC/DEHP
Products in Healthcare
AMA: (1) encourages hospitals and physicians to reduce
and phase out polyvinyl chloride (PVC) medical device
products, especially those containing Di(2-
ethylhexyl)phthalate (DEHP), and urge adoption of
safe, cost-effective, alternative products where
available; and (2) urges expanded manufacturer
development of safe, cost-effective alternative
products to PVC medical device products, especially
those containing DEHP. (BOT Action in response to
referred for decision Res. 502, A-06)

Webinar,
24/09/2014
Summarising
– Clear indications of DEHP exposure from medical devices
– Animal studies show negative health effects
– Exposure scenario in plastic laden environment
– Increased exposure in infants

Webinar,
24/09/2014
Precautionary
Principle
– Safer alternatives for almost all products
– We need to actively choose better alternatives
– Choose PVC-free/DEHP-free
– “When in doubt, throw it out”

Webinar,
24/09/2014
Database
Glucose 3.75%-NaCl 0.225% IV bags PVC-Free
Voluven IV bags PVC-Free
NaCl 0.9% IV bags PVC-Free
Glucose 20% IV bags Non-PVC
Metronidazol 5mg/ml IV bags Non-PVC
Gelofusine IV bags Ecobag® PVC-vrij
Air Inlet Needle With Valve PVC-Free
Infuus Medi-Cath 24G Intravenous Cannula
BD Neoflon 24G Intravenous Cannula
BD Vasculon 22G Intravenous Cannula
Bioflow 24G Intravenous Cannula
Microflex Infusion Set 27G

Not easy …
London,
18/11/2011

London,
18/11/2011

Webinar,
24/09/2014
Concluding
– Our children are already being exposed to
chemicals in concentrations that are too high
– It is not wise to risk the health and development
of our children

Webinar,
24/09/2014
Take home
message
– Let us learn from our mistakes and implement these
lessons with other chemicals, especially when treating our
patients
– First do no harm !!!
– Thank you for your attention!

To find PVC/phthalate-free alternatives:
safermedicaldevices.org
For more on EDCs:
noharm-europe.org
EDCs Free campaign page:
edc-free-europe.org
Global Green and Healthy Hospitals:
greenhospitals.net

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Endocrine disruptors in the healthcare sector

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