Hazardous chemicals in our Blood
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an educational material about phthalates, their use in medical devices and their harmful effects
by Eline Aggerholm Kristensen
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Hazardous chemicals in our Blood
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Hazardous chemicals in our blood – an Introduction
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The Chemistry of the Phthalates
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The Harmful effects of the Phthalates
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Phthalates in Medical Devices
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Legislation on phthalates
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Phthalates can be replaced
ColoPhon
Published by
Hazardous chemicals in our Blood – an educational material about phthalates, their use in medical devices and their harmful effects
The publication, along with a teaching manual in Danish, can be downloaded from The Ecological Council’s website: www. ecocouncil.dk
1st issue, January 2014 ISBN: 978-87-92044-63-1
The documentary can be viewed on youtube by using following links: Long version: http://goo.gl/VnRJ77 Short version: http://goo.gl/Xg9wp5
Text by Eline Aggerholm Kristensen, The Ecological Council Translation Maggie Watts, Eline Aggerholm Kristensen Layout Maria Gry R. Bøndergaard Printed by KLS Grafisk Hus A/S
Quoting, copying and other use of the content of this publication is permitted so long as credit is given to its source.
The Ecological Council – with funding from the Ministry of Education Tips and Lotto Fund, The Villum Foundation, The R98 Foundation and Europanævnet. The Ecological Council Blegdamsvej 4B DK-2200 Copenhagen N Tel. +45 3315 0977 info@ecocouncil.dk www.ecocouncil.dk
Hazardous chemicals in our Blood
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Hazardous chemicals in our blood - introduction We are surrounded by industrially produced chemicals. They are found in most of the consumer products that we surround ourselves with. In many instances the chemicals make life better and easier for us, but some of the chemicals have unfortunate or directly harmful effects to our health. For example, some can cause cancer, some cause problems with allergies, and others affect the endocrine systems of both humans and animals in unwanted and unexpected ways. The last group is called endocrine disrupting chemicals. Phthalates are a subgroup within a group of chemicals that are suspected of disrupting endocrine function. Phthalates are added to PVC to make the plastic material softer. They are used in particular in hospitals where the blood transfusion bags, tubes, catheters and other devices require materials to be soft. Unfortunately, phthalates can have a negative impact on patients’ health when they are absorbed into the body. Research suggests that they can harm fertility and the sperm quality of men, cause behavioural disorders, liver damage, obesity and various types of cancer. Phthalates are particularly harmful to pregnant women, children and premature babies as well as chronically ill persons. For this reason it is especially unfortunate that these vulnerable patients risk receiving phthalates in their blood via medical devices. There is a lot of research that has demonstrated the endocrine disrupting effects of phthalates, and there are alternatives to phthalates which have not demonstrated these same effects. Despite this, the use of phthalates is still permitted in medical devices. It is actually possible to phase out the use of phthalates. When one can avoid the use of a worrying chemical, it seems senseless to expose patients to close contact with these endocrine disrupting chemicals. In the documentary, �Hazardous Chemicals in our Blood� researchers, politicians and representatives of environmental organisations explain their views on phthalates. This publication, which accompanies the documentary, discusses the chemistry of phthalates, the scientific basis of the detrimental effects to health, the legislation and the alternatives to phthalates. The Ecological Council January 2014
Hazardous chemicals in our Blood
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The Chemistry of Phthalates Phthalates are a group of esters of phthalic acid. They are made from mineral oils and are generally used to increase the flexibility, adhesiveness and pliability of plastic-based consumer products. They are especially used in conjunction with polyvinylchloride-plastic (also known as PVC) to make it soft and pliable. PVC is a polymer that consists of many vinyl chloride molecules joined together in a long chain (see figure 1). This is a very rigid material, which needs to be softened if it is usable, for example, in medical tubes or other soft plastic products like rain clothes, wellingtons, floor coverings, children’s toys, shower curtains, wax tablecloths, print on T-shirts etc. Besides, phthalates are found in a range of other things including cosmetics, medicines and paint, where they are mostly used for their adhesiveness. Phthalates soften PVC because they facilitate movement in and between the polyvinylchloride chains. Phthalates are synthesised from a simple condensation reaction between alcohol and carboxylic acid with the release of a water molecule. They have no or a very light smell and are increasingly fat-soluble (lipophilic) depending on how long
their chain is. There are many different chain lengths, but it tends to be the longer chained phthalates that are used as plasticizers and the shorter chained ones are used in cosmetics. People are exposed to many phthalates because they are used in so many everyday products. Besides this they are easily released because they are only bonded to PVC by weak electrical forces that fade over the lifetime of the material (box 1). Soft PVC products typically contain up to 40% phthalates and are therefore able to release large amounts during the product’s lifetime. Phthalate molecules are thus released over time into the surrounding environment, for example the air, water and other fluids, skin or foodstuffs. This is the reason that PVC materials become more brittle and fragile over time. Studies have shown that everyday house dust contains large amounts of phthalates1 which are released from PVC products such as vinyl flooring. A study shows that tubing used to transport oxygen to the lungs (endotracheal tubes) after use had lost up to 12% of their content of the phthalate di(2ethylhexyl)phthalate (DEHP)2.
Standard formulas for PVC and phthalate
PVC Phthalate
Vinyl chloride: CH2 = CHCI Polyvinyl chloride: -CH2-CHCI-CH2-CHCI-CH2-CHCI
Figure 1. PVC consists of many vinyl chloride molecules (CH2=CHCl) on a long chain. At the right-hand side of the figure the structure of a phthalate is shown
Report from ChemSec og Svensk Naturskyddsföreningen (2011): http://www.chemsec.org/images/stories/2011/chemsec/ home_sweet_home_lowres.pdf
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Latini G and Avery G. 1999. Materials degradation in endotracheal tubes: a potential contributor to bronchopulmonary disease (letter). Acta Paeditr, 88:1174-1175.
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Hazardous chemicals in our Blood
Phthalates binding to PVC
The phthalates are bound to the PVC through weak electrical forces. These forces occur because both the PVC and the phthalates have some imbalances in the distribution of electrons. Oxygen atoms in the phthalates and chlorine atoms in the PVC pull in those electrons that are shared with their neighboring atoms, whereby partial negative and partial positive charges occur. The partial negative charges in the phthalates are attracted to the partial positive in the PVC and vice versa. Such weak electrical bonds between neutral molecules are called Van der Waals forces. Soft PVC products contain up to 40 % phthalates. Example of a partial electrical bond between two molecules wherein oxygen atoms pull the electrons from neighboring atoms leading to partial charges.
Phthalate Polyvinylchloride
Box 1. Shows how phthalates are attracted to PVC via weak partial electrical forces
Name
Acronym Structural formula CAS NUMBER
Dimethyl phthalate
DMP
C6H4(COOCH3)2
131-11-3
Diethyl phthalate
DEP
C6H4(COOC2H5)2
84-66-2
Di-n-propyl phthalate
DPP
C6H4[COO(CH2]2CH3)2
131-16-8
Di-n-butyl phthalate
DBP
C6H4[COO(CH2]3CH3)2
84-74-2
Diisobutyl phthalate
DIBP
C6H4[COOCH2CH(CH3)2 ]2
84-69-5
Benzyl butyl phthalate
BBP
CH3(CH2)3OOCC6H4COOCH2C6H5
85-68-7
Butyl decyl phthalate
BBP
CH3(CH2)3OOCC6H4COOCH2C6H5
89-19-0
Di(2-ethylhexyl) phthalate
DEHP
C6H4[COOCH2CH(C2H5)(CH2)3CH3]2
117-81-7
Diisononyl phthalate
DINP
C6H4[COO(CH2)6CH(CH3)2]2
28553-12-0
Diisodecyl phthalate
DIDP
C6H4[COO(CH2)7CH(CH3)2]2
26761-40-0
Figure 2. Eksamples of phthalates with their abbreviations, structural formulas and CAS numbers
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Hazardous chemicals in our Blood
The Harmful Effects of Phthalates In 2006 Greenpeace studied a number of famous Danish people’s blood for specific chemicals and found on average three types of phthalates in each sample. The study Greenpeace carried out is not scientific, but it gives reason to assume that most Danes have phthalates in their blood. Other, more scientific studies have also shown the presence of phthalates and their metabolites in urine, blood from the umbilical cord, amniotic fluid, saliva, breast milk and placental tissue in humans. There is a great deal of research into the harmful effects of phthalates. There are thousands of animal studies (in vivo), but many aspects need to be taken into consideration, such as phthalate type, method of exposure (via the skin, through food and breast milk or breathing etc.), concentration, the duration of the exposure (acute or over months/years/generations), the type of animal used etc. Even with the results, the question remains as to how they are applied, as it is not possible to directly transfer animal studies to humans. There are many differences between laboratory research and the real world. People are exposed to a mixture of chemicals, whereas research animals are often only exposed to the chemical one wishes to research. Besides, humans break down phthalates and other chemicals differently compared to other animals, and disease processes are often different between different
Swan et al. 2005. Decrease in Anogenital Distance among Male Infants with Prenatal Phthalate Exposure. Environ Health Perspect, 113(8): 1056–10614 4 Duty et al. 2003. Phthalate Exposure and Human Semen Parameters. Epidemiology 14:269 –277 5 Tranfo et asl. 2012. Urinary phthalate monoesters concentration in couples with infertility problems. Toxicol Lett. 213(1):15-20 6 Wolff et al. 2010. Investigation of Relationships between Urinary Biomarkers of Phytoestrogens, Phthalates, and Phenols and Pubertal Stages in Girls. Environ Health Perspect 118(7): 1039–1046 3
species. The animal studies can be used to give an indication of which effects the phthalates might have in humans. To examine more directly whether phthalates have detrimental effects on health in humans, it is possible to undertake for example biomonitoring studies, where biomarkers (e.g. the level of specific enzymes in the blood) are measured in subjects where it is known that they have a high phthalate level in the blood. Epidemiological studies (e.g. where a population has been exposed to a specific chemical pollutant) are often used, because a large number of subjects are followed, which makes the results more reliable. Several epidemiological studies have found correlations between exposure to phthalates and malformations of the male reproductive system3, decreased sperm production4 and fertility5, early puberty in girls6, asthma7, obesity8 and effects on the thyroid9. There are also in vitro studies, where chemicals can be screened. This provides a superficial view of a large group of chemicals by testing them on a cell line. Testing a chemical on e.g. lung cells is relevant if one is studying the effect of inhaling a chemical. In vitro is useful because it is quick and cheap and uses few or no animals. It gives an idea of how chemicals work regarding a particular biological endpoint and can lead to suspicion that a particular chemical is harmful to health. A limitation of in vitro screenings is that they
Just et al. 2012. Children’s Urinary Phthalate Metabolites and Fractional Exhaled Nitric Oxide in an Urban Cohort. American Journal of Respiratory and Critical Care Medicine, 186:9 830 8 Teitelbaum et al. 2012. Associations between phthalate metabolite urinary concentrations and body size measures in New York City children. Environmental Research, 112:186-93 9 Whyatt et al. 2012. Maternal Prenatal Urinary Phthalate Metabolite Concentrations and Child Mental, Psychomotor, and Behavioral Development at 3 Years of Age. Environmental Health Perspectives, 120:2 290-29 7
Hazardous chemicals in our Blood
only reveal information regarding the particular effect being studied and do not reveal anything about other harmful effects. For example, a harmful effect could be found in lung cells, but this would not tell us anything about possible effects on e.g. blood vessels. Phthalates have several modes of action, but the most problematic is that they can work in the same way as estrogens (female sex hormones) in the body or work like anti-androgens (suppressing male sex hormones). Phthalates can also affect the production, transport and elimination of the body’s own hormones. The endocrine effects have many different modes of action, for example: • mimicking the mode of action of the body’s own natural hormones • blocking the mode of action of the body’s own natural hormones • affecting the body’s metabolism of the body’s own natural hormones, so that they work for a longer or a shorter time than normal • affecting the synthesis (formation) of the body’s own natural hormones, so that the body is exposed to higher or lower than normal levels • affecting the transport of the body’s own natural hormones, so that they, for example, do not get transported to the part of the body where they work (which might be the brain) These mechanisms are divided into three main categories: 1) T hey can mimic the effect of a naturally produced hormone like estrogen or testosterone. This can trigger similar reactions in the body. (Agonism) 2) T hey can block receptors in the cells that bind hormones and by doing so stop the action of the body’s naturally occurring hormones. (Antagonism)
Harmfull effects of phthalates
Hypospadias incomplete development of the urethra so that the opening of the urethra is at varying distances from the penis head. The malformation is accompanied by split foreskin and in some cases of a curvature of the penis Cryptorchidism a condition in which the testes have not descended into the scrotum at birth Reduced sperm quality 40 % of young otherwise healthy Danish men have decreased sperm quality, which can cause fertility problems. 6 % have such poor sperm quality that they cannot have children without assistance Testicular and breast cancer hormone-related diseases obesity and insulin resistance there has been shown a connection between these conditions and the level of metabolites (products from metabolism) from phthalates in men. It is suggested that especially exposure to phthalates and other endocrine disruptors - in the fetal stage, increases the risk of obesity later in life Feminization effects of endocrine disrupting chemicals seen in rodents, fish and amphibians - e.g. reduced distance between the anus and the basis of the penis
Figure 3. Examples of (suspected) harmful effects of phthalates. Some effects have been demonstrated using animal studies (e.g. cryptorchidism and various types of cancer) while others are suspected of being caused by phthalates and other endocrine disrupting chemicals (e.g. reduced sperm quality)
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Hazardous chemicals in our Blood
Prevalence of hypospadia (%)
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0.56 0.55 0.54 0.53 0.52 0.51 0.50 0.49 0.48 0.47 0.46 0.45 0.44 0.43 0.42 0.41 0.40 0.39 0.38 0.37 0.36 0.35 0.34 0.33 0.32 0.31 0.30 0.29 0.28 0.27 0.26 0.25 0.24 0.23 1977
Observed prevalence (%)
1980
1985
Trend
1990
1995
2000
2005
Year
Figure 4. Observed prevalence of hypospadias in newborn Danish boys, 1977-2005. Source: Lund, L. et al. 2009. Prevalence of Hypospadias in Danish Boys: A Longitudinal Study, 1977–2005. European Urology 55:1022-1026
3) They can affect the synthesis, transport and metabolism and/or elimination of the hormones, thereby affecting the concentration of the body’s natural hormones.
Endocrine disrupting chemicals can mimic the body’s natural hormones in different ways: Estrogen-like effect: The naturally occurring female hormones are estradiol, estriol and estrone, together called estrogens. The hormones work by binding to their specific receptors. When that binding occurs in the right way, an endocrine response is triggered. Chemicals with an estrogenlike effect can be particularly harmful for male
fetuses because they can only tolerate a low level of estrogen. Anti-Androgen effect: Anti-androgens work by counteracting the natural way testosterone and the other male sex hormones function. This counteracting function is particularly critical for male fetuses because it can lead to the incomplete development of, in particular, the genitals. Effects on the thyroid: Chemicals can have a disturbing effect on the thyroid hormones’ (thyroxine and tri-iodothyronine) transport and metabolism. Amongst other things, this can affect the brain development of the fetus, if the mother is exposed to these chemicals. In addition, this
Hazardous chemicals in our Blood
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Figure 5. A statistical picture of the development of testicular cancer (kræft) in the Nordic countries. The rate is the number of new cases or deaths per 100 000 population per annum. An age standardised rate is the rate the population would have if they had a standardised age distribution. It is necessary to standardise the age structure to compare the figures because age is an important factor in the development of testicular cancer. Source: Patama T, Engholm G, Klint Å, Larønningen S, Ólafsdóttir E, Christensen N, Storm H, Pukkala E (2013). Small-area based map animations of cancer incidence in the Nordic countries, 19712010. Nordic Cancer Union: http://astra.cancer.fi/cancermaps/Nordic, accessed on 17/4/2013.
group of endocrine disruptors can predispose a fetus for a life of obesity10. This happens due to a decrease in thyroxine production, which in turn decreases the resting metabolic rate, which affects the overall conversion of energy. Some phthalates have been demonstrated to be endocrine disrupting and some are suspected of being so. Apart from that, phthalates can cause mutations in cell’s DNA (mutagenic effect) and amongst other things increase the risk of cancer Teitelbaum, S.L. et al. 2012. Associations between phthalate metabolite urinary concentrations and body size measures in New York City children. Environmental Research, 112:186–193 11 Zama, A.M et al. 2010. Epigenetic effects of endocrine-disrupting chemicals on female reproduction: An ovarian perspecti10
(carcinogenic effect). Furthermore, new research shows that phthalates can have an epigenetic effect on our DNA11, which amongst other things is linked to the development obesity12. An endocrine disrupting chemical affects the endocrine system of humans and animals that come into contact with it. This can be extremely serious both for the organism affected, and for its offspring.
ve. Front Neuroendocrinol 31(4): 420–439 Manikkam, M. 2013. Plastics Derived Endocrine Disruptors (BPA, DEHP and DBP) Induce Epigenetic Transgenerational Inheritance of Obesity, Reproductive Disease and Sperm Epimutations. PLOS ONE 8:1
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What is an endocrine disrupting chemical? An ED (Endocrine Disruptor) is an exogenous chemical, or mixture of chemicals, that interferes with any aspect of hormone action.
– The Endocrine Society 2012
This definition is proposed by The Endocrine Society, a worldwide organization dedicated to scientific research in Endocrinology. In EU law there is no agreed definition of what an endocrine disrupting chemical is. It is expected that a definition will be agreed upon by the EU Commission earliest by 2015.
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At the same time in the field of human medicine, there was awareness of an increasing incidence of testicular cancer, poor sperm quality and cryptorchidism (the testicles have not descended into the scrotum at birth). In 1993 Professor Dr. med. Niels Erik Skakkebæk from Rigshospitalet in Denmark proposed the estrogen hypothesis in the well-known journal The Lancet together with his colleague Professor Richard Sharpe from the Medical Research Council in Edinburgh13. They formulated and substantiated the theory that males can have their reproductive ability completely or partly damaged if they are exposed either to the hormone estrogen, or to chemicals that are estrogen-like. Today there is a great deal of research that supports the estrogen hypothesis and it is well documented that the endocrine disrupting chemicals can have a big effect even at very low concentrations – the so-called ‘low dose effect’. A group of American researchers published a report in March 2012 called The Vandenberg Report14. This provides an overview of over 100 scientific studies that demonstrate, that endocrine disrupting chemicals in many instances cause harm at low
Sharpe, R.M. and Skakkebaek, N.E. 1993. Are oestrogens involved in falling sperm counts and disorders of the male reproductive tract? Lancet 29;341(8857):1392-5.
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Non-monitonic dose-response curves
Response
In 1980 it was first realised that hormone-like chemicals could harm the reproduction capability in both animals and humans. In nature there were examples such as hermaphroditism in fish and other aquatic animals. The American biologist Theo Colburn from the World Wide Fund for Nature (WWF), now Professor Emeritus at the University of Florida, was the first to draw attention to the possible connection between reproduction abnormalities in animals and the estrogen or estrogen-like chemicals in the environment after finding an alarming number of reproductive problems in fish in the Great Lakes on the border between Canada and the USA.
concentrations without necessarily having an effect at higher concentrations. The report also showed that the chemicals do not always follow a linear dose-response curve, but instead can follow a non-monotonic dose-response curve (figure 6).
Response
The Historical Perspective
Dose
Dose
Figure 6. Examples of non-monotonic dose-response curves
Phthalates are broken down fairly easily to their metabolites (phthalate monoesters) and are then eliminated from the organism. Therefore, it requires a daily exposure to phthalates for a measurable level to be recorded in, for example, blood or urine. Harmful effects of the metabolites have also been demonstrated.
Greatest effect on children There is general agreement that exposure as a fetus to a greater extent increases the risk for serious and permanent changes in humans and animals compared to exposure as an adult. The endocrine system is important throughout life, but a well-functioning endocrine system is critical for the normal development of a fetus and a child. The endocrine system controls the development of the fetus, including the development of
Vandenberg et al. 2012. Hormones and Endocrine-Disrupting Chemicals: Low-Dose Effects and Nonmonotonic Dose Responses. Endocrine Reviews March 14, 2011-1050tract? Lancet 29;341(8857):1392-5.
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organs. This makes the fetal stage the most vulnerable to hormonal disturbances. Furthermore, children are affected at lower levels than adults are, and they are at the same time exposed to higher concentrations. Phthalates are unfortunately found everywhere. In 2003 the Danish Veterinary and Food Administration investigated the combined daily exposure of the phthalates DEHP, DBP, BBP, DINP and DIDP, and found it to be 96.8 µg/kg bodyweight/day for adults, but nearly one hundred times as high for children aged 6-12 months, in fact 927 µg/kg bodyweight/day15. The much higher levels of exposure in small children is primarily due to the fact that they crawl on the dusty floor and inhale particles from the indoor environment which contains large amounts of chemicals. Children suck on their hands and on things that lie on the floor. Thereby, they intake large amounts of house dust and are much more exposed to the worrying chemicals than adults are.
The Estrogen Hypothesis Male reproductive disorders and/ or incomplete development of reproductive organs is due to exposure to estrogens or estrogen-like chemicals at a critical time during fetal development – Sharpe & Skakkebæk, 1993
There is research that suggests that poor sperm quality in adult men could be caused by exposure to endocrine disrupting chemicals in the embryonic stage16. Therefore, there is extra reason to pay close attention to phthalates in the equipment that premature babies and small children
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Müller et al. 2003. Human exposure to selected phthalates in Denmark. FødevareRapport 2003:15, Fødevarestyrelsen 16 Shanna H. Swan, S.H., 2008. Environmental phthalate
come into contact with at the hospital. Besides, it is also very problematic if pregnant and breastfeeding women are exposed to phthalates, because fetuses and babies can be exposed through the placenta or breast milk, respectively. Another problem is the risk of a cocktail effect of various chemicals. In brief, a cocktail effect occurs when you are exposed to several chemicals at the same time (e.g. when children play on the floor and breathe in house dust). The effect of this exposure can be different to being exposed to each chemical individually. Cocktail effects are still not included in the risk assessments of chemicals.
Phthalates in the Enviroment Phthalates and their metabolites eventually end up in the environment and therefore also in the food chain. The release occurs through rain or sewage treatment plants. The lipophilic phthalates bind to organic particles and settles as part of the sediment. In the sewage treatment plants they are bound to sludge (as an unintended form of pollution) that is later used as fertilizer on agricultural land. For this reason soil and sediment often contain high concentrations of phthalates. Some phthalates bioaccumulate and are found in aquatic animals, and this has been seen in male examples of fish, frogs and other amphibians that have lived in phthalate polluted water environments. These have been found with ovaries instead of testicles. These are adverse effects, which - as per the estrogen hypothesis - are assumed to be a result of the endocrine disrupting effects of phthalates. Thus, there are many good reasons to phase out the use of phthalates as additives, but it would also be an advantage to find an alternative to
exposure in relation to reproductive outcomes and other health endpoints in humans. Environ Res. 108(2): 177–184
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FACTS on endocrine disrupting chemicals • Endocrine disrupting chemicals are chemicals that either work in the same way as the body’s own natural hormones, or affect the level of the natural hormones in the body. • It is suspected that the chemicals harm fertility and amongst other things decrease sperm quality and cause gender related cancers and malformed genitalia in both animals and humans.
• The chemicals are found in many different products such as food, food packaging, cosmetics, hospital equipment, toys, electronic equipment, washing detergent, paint and many other items. • The EU has produced a list of 564 chemicals that are suspected of being endocrine disruptors. The phthalates are on the list. They need to be researched further, but at the moment are only subject to minimal regulation (especially toys). This is because the EU does not have a clear definition of what an endocrine disrupting chemical is, neither does it have clear criteria for how this should be tested. The definition and criteria are expected in 2014. • The phthalate DEHP is already on the authorisation list in the EU, but this is based on the fact that the chemical is believed to impair fertility.
Box 2.
the PVC plastic itself. PVC often contains heavy metals (as stabilisers) and because of this it is not appropriate for re-use. And because of the phthalates, that leak out, it is not appropriate for disposal. In the incinerator, hydrochloric acid and dioxins can be released. The hydrochloric acid is neutralized in Danish incinerators, but the residual products require special deposits to prevent pollution of the ground water. Most dioxins are broken down or are caught in filters, but dioxins are extremely poisonous, and the filter material also needs to be deposited.
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Phthalates in Medical Devices PVC plastic with phthalates has many good properties and fulfills many criteria required of hospital equipment. The material is flexible and transparent and it can be centrifuged and welded. Apart from that it is relatively cheap, and for that reason it is a success worldwide. Most medical devices are made of PVC with added phthalates - e.g. bags for storage of blood or other fluids for infusion or nutrition, but also pipes and tubing, catheters, single-use gloves and many other items. PVC for most medical devices contains approximately 20-40 % phthalates (by weight) while PVC tubing can contain up to 80 %. It is primarily DEHP that is used for these applications. The normal method of exposure to phthalates and other chemicals is through tiny tears in the skin or through the respiratory system. In the body, the skin, pleura and cell membranes act as barriers that limit the uptake of phthalates. Some chemicals get through these barriers and into the blood. They are then transported through the body where they can cause harm. Some phthalates can even accumulate in the
Phthalates in medical devices. Exposure to phthalates happens in many ways. Through the use of phthalates in medical devices, for example, dialysis patients risk a high level of exposure to phthalates directly into the blood via contamination from the tubing used.
womb (uterus) and be transferred to the fetus during pregnancy. In hospitals patients are also exposed intravenously when there are phthalates in the plastic bags used to store blood and nutrient solutions, as well as in tubing and catheters etc. Thus they receive phthalates directly into the blood. This happens because the phthalates are not chemically bound to the PVC and are easily released from the plastic when the device comes into contact with liquids, fats and/or heat. This is because phthalates are lipophilic and are attracted to fatty solutions, for example blood and nutrient solutions. Long-term patients, or patients regularly receiving treatment, are particularly at risk of exposure to phthalates, especially treatments involving blood transfusion, hemodialysis or nutrient infusions. Of these, the most vulnerable are kidney patients. The kidneys work to clean the blood and if the kidneys fail, the patient will need dialysis. Dialysis involves long-term contact between blood and tubing, and with that, a high risk that the patient will absorb the phthalates that are released from the plastic. Another particularly vulnerable group is premature babies in the intensive care unit. They need intensive help to survive. Some need help to breathe and are put on a ventilator with a tube through their mouth down into their trachea. Many premature babies also have a venflon put in. This is a thin plastic catheter put into a vein. Through this, the baby receives electrolyte fluids and medicine directly into the bloodstream. They often require blood transfusions, oxygenation of the blood by a technique called Extra Corporeal Membrane Oxygenation (ECMO) and they are often fed through gavage (enteral nutrition). Infusion of nutrients directly into the blood (parenteral nutrition) is another area that leads to high levels of exposure. Premature babies are
Hazardous chemicals in our Blood 15
Cross-section of phthalate-containing PVC blood bag
Phthalate-molecule Blood
Different types of treatments for premature babies
Figure 7. Cross-section of a PVC blood bag that shows how the phthalate molecules migrate from the plastic into the blood
therefore exposed to phthalates through many different routes and often these are directly into the blood. The endocrine system plays a critical role in the early developmental stages, and premature babies are particularly vulnerable to endocrine disrupting chemicals. They have less effective blood-brain and blood-testicle barriers. This means that the chemicals move more easily from the blood to either the brain or the testicles. The metabolism of the premature babies is not completely matured, so they have difficulty in getting rid of the phthalates and the metabolites. The enzyme lipase normally breaks down phthalates and other lipids in the body. It is produced in the pancreas, but premature babies have lower levels of this enzyme. On top of that, the concentration of phthalates in the body is higher in children – especially in premature babies - than in adults because the amount of body fat in a child is much lower. Premature babies are thus very vulnerable to phthalates, but at the same time exposed to high levels in hospitals due to the medical devices used. They are typically exposed to levels of DEHP which exceed the levels that have been
17
Latini et al. 1999. Materials degradation in endotracheal tubes: a potential contributor to bronchopulmonary disease (letter). Acta Paeditr, 88: 1174-1175
· Blood transfusion
· Electrolyte infusion
· Total parenteral nutrition
· Blood infusion
· Medicine
· Enteral nutrition
· Respirator
· ECMO
Figure 8. The different types of treatment involving PVC products and thereby a risk of transference of phthalates to the blood. ECMO: a heart-lung machine takes over the function of the heart and lungs to give these organs a chance to fully develop; electrolyte infusion: this is given to stabilise the fluid and ion balance; enteral nutrition: given through gavage into the gastrointestinal tract; total parenteral nutrition: nutrition given via the blood - this is used when nutrients cannot be ingested, digested or absorbed.
demonstrated to not cause health problems in animal studies (NOAEL). Studies have shown that the tubing used for the ventilation of premature babies’ lungs released 6-12 % DEHP during use17. Studies have also found DEHP in the lungs of babies following mechanical ventilation, so it is reasonable to assume that the chemicals that are released from the device accumulate in the lungs. In addition, studies17 have shown that while adult humans under normal circumstances are exposed to 3-30 µg DEHP /kg bodyweight/ day, premature babies can be exposed to 40-140 µg DEHP /kg bodyweight/day when they receive
Personal communication with Dr.med. Gavin Ten Tusscher, Westfriesgasthuis, Holland
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enteral nutrition, and be exposed to 2500 µg DEHP /kg bodyweight/day when they receive total parenteral nutrition. Such an exposure can be several hundred times higher than those recommended by the authorities. In conjunction with
the fact that premature babies often receive gavage over a long period of time, this one route of exposure can lead to a high DEHP burden on the newborn baby’s health.
Legislation on phthalates In Denmark it is completely legal to use medical devices made of PVC containing phthalates even though it has been known for 30 years that phthalates are released and absorbed by the body19. Denmark cannot pass its own laws in this area, as it is subject to the legislation of the EU. The use of medical devices is regulated by three EU-directives which are under review at present (2012-2014) and will be replaced by specific regulations. None of the three directives contain restrictions on the use of phthalates or other endocrine disrupting chemicals. The new regulations are under discussion in the EU. Changes to the current regulation proposals have been agreed upon at a plenary session in October 2013. These include a ban on carcinogenic, mutagenic, reproduction toxic and endocrine disrupting chemicals in invasive medical equipment and devices used to administer, transport or deliver medicine, bodily fluids or other chemicals. The changes allow for the hazardous chemicals to remain in medical devices for a maximum of four years during an exemption process. Chemicals in medical devices are partly regulated by the EU chemicals legislation, REACH. But even REACH does not ban the endocrine disrupting chemicals in medical devices.
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DEHP appears on many warning lists, including the European Candidate list and the Authorisation list under the EU chemicals legislation REACH, the Danish EPA’s list of undesirable substances (LOUS) and the EU’s priority list of potential endocrine disrupting chemicals. In 2011 Denmark planned to ban four phthalates – DEHP, DBP, BBP and DIBP – from a long list of consumer products and proposed that in the future the four chemicals should be banned throughout the EU. The proposal was based on cocktail effects of chemicals. Phthalates in medical devices were not included in the ban. Two committees in the EU - the Risk Assessment Committee (RAC) and the Committee for Socio-Economic Analysis (SEAC) assessed the proposals and stated that there was insufficient data to support them. The Danish Government took the issue further and imposed a national ban of the four phthalates in a wide range of product groups (though still excluding medical devices). The National ban was to be implemented December 2013, but the Government decided to postpone the ban for two years due to pressure from industry. France is the only country in the EU that has a DEHP ban on tubing used in pediatric, neonatal and obstetric units starting in 2015, but the French ban has still not been accepted by the EU Commission.
Kevy et al. 1981. The need for a new plasticizer for polyvinyl chloride medical devices. Trans Am Soc Artif intern Organs, 27:386-390
This issue is crucial but unfortunately it does not seem on the radar screen of the European decision makers. We need to reinforce the rules before and after the placing on the market and we need an ambitious legislation on this issue. – Corinne Lepage, Member of the European Parliament Workshop at the European Parliament on medical devices, March 2013
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Since 2007 in the EU there has been specific rules regarding phthalates in toys for children aged 3-14 years. The phthalates DEHP, DBP and BBP cannot be used in toys or products for small children in concentrations above 0.1 % by weight and the phthalates DINP, DIDP and DNOP are banned in toys at the same threshold if children are able to put them into their mouths. Apart from this, since 1999, Denmark has had special rules regarding toys for small children and it is
thus illegal to import, sell or use toys or other products for children aged 0-3 years if the level of phthalates is above 0.05 % by weight. The ban also includes other children’s products, for example nursing pillows, carrying harnesses, dummies and bathing equipment. After phthalates were banned in toys, the manufacturers have moved away from PVC and use other materials including polyethylene, polyester and silicone, which are good alternatives.
Phthalates can be replaced Even if phthalates have an important function as plasticizers, it is possible to manage without them. There are other less dangerous or completely harmless chemicals on the market that can replace both the phthalates and the PVC plastic itself and it would be a big advantage for the environment to phase out both. Many businesses offer phthalate- and PVC-free alternatives within medical devices, or alternative plasticizers. An example is a non-toxic plasticizer, developed by the then Danish company Danisco (now American Dupont), based on American oil. Another example is a phthalate-free plastic granule used
There are no alternatives to the phthalates that are used in blood bags, but the EU is supporting a project that hopes to have a finished alternative product by 2015.
in medical devices from the Danish company MELITEK. Examples of alternatives to phthalate softened PVC include polyethylene, polypropylene, polyester, silicone and metallocene-based polyolefin.
Examples of hospitals, which are replacing phthalates Many hospitals already use phthalate-free products. Since 2005, in the Hospital of Southern Jutland there has been a general focus on procuring products without DEHP. In the neonatal unit, they use phthalate-free catheters, intravenous tubing, tongue depressors, nutritional tubing and bandages amongst other things. In the beginning the alternative products were 2½ to 3 times more expensive, but now there is no difference in price. The quality and practicality of the alternatives are the same as the ones containing phthalates and they have no bad experiences with the new products. In Hoorn in Holland the hospital Westfriesgasthuis’ children’s unit is totally PVC- and phthalate-free with the exception of blood bags. Another example is the neonatal unit at the Children’s hospital Glanzing in
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Vienna, Austria20. They began their PVC replacement project in 2001. The amount of PVC-based devices in the hospital constituted 343 kg in 2001 and 178 kg in 2010. This is nearly a halving of PVC-based devices. More examples can be found in the publications of Health Care Without Harm (www.noharm.org) and on the Danish website http://www.eco-forum.dk/medicoartikler/ by the Danish EPA. Blood bags are one of the only products with no good alternatives to the phthalate containing plastic. In the EU-funded project ”PVCFreeBloodBag” - which continues until 2015 - researchers are developing a PVC- and phthalate-free blood bag. The project includes many manufacturers, among others Danish Totax Plastics A/S and MELITEK A/S, Italian Haemotronic S.p.A. and Finnish Wipak Medical.
Barriers Blood transfusions are one of the medical treatments that save most lives and for that reason blood bags are subject to high demands. The plastic material must not affect the quality of the blood, it must be able to cope with temperatures up to 70 °C and it needs to tolerate being sterilised. Besides, it should be able to manage centrifugation in an ultracentrifuge that operates at speeds up to 5000 the relative centrifugal force (5000 times g). An extra advantage of the traditional blood bags is that the phthalate DEHP has a stabilising effect on the membrane of the red blood cell, which reduces hemolysis. This increases the shelf life of the blood. Even though there is no doubt that there are advantages to substituting the phthalates, there is no guaran-
Lischka, A. et al. 2011. Substituting Phthalates in Plastic Medical Devices: The Austrian Experience-PVC-Free Neonatal Intensive Care Unit of Children’s Hospital Glanzing in Vienna.
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tee that the alternative plasticizers do not also leach from the PVC. It requires extensive research to ensure that an endocrine disrupting chemical is not merely replaced by another hazardous chemical.
Figure 9. Soft plastic like PVC is softened using phthalates. Ranges of phthalates are endocrine disruptors, or are suspected of being so. A lot of plastic (especially packaging) has a logo made of three arrows and a number, and PVC has the number 3. The marking is not compulsory in Denmark.
The problem with the alternatives is that there are relatively few of them compared to the traditional products and in some cases they are more expensive. It is important for hospitals that medical devices live up to high technical standards and that they are relatively inexpensive. If the phthalate-free products are technically inferior to the traditional ones (e.g. they are more stiff) and more expensive, the hospitals will not buy them. For manufacturers to spend time and money developing high quality phthalate-free medical devices, there needs to be a demand for them, which is lacking as long as the alternatives are more expensive, and phthalates are still permitted. A change in the law from Denmark or the EU would assist the development of alternatives and enable competitive prices.
Journal of Environmental Science and Engineering, 5, 11621166
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Cables at NKT Cables
Green Taxes and Economic Incentives Increased competition on the market will promote development and ensure that there are products of a high quality at competitive prices. As long as phthalates are not banned, development of the alternative products can be promoted by placing green taxes on the phthalate containing products. In 2000 Denmark introduced a PVC and phthalate tax. The tax is approximately 0.27 euros per kilo of PVC and 0.94 euros per kilo of phthalates. The intention was to decrease the use of phthalates and this was achieved in many areas, for example in cable production. The Danish company NKT Cables has developed cables in which the lead-stabilised and the phthalate softened PVC has been replaced with a new, less harmful product. Their cable NOPOVIC速 is based on a mixture of halogen-free polymers, without added flammable minerals (e.g. magnesium or aluminium hydrates). The phthalate free cables can compete on price because there are no green taxes on them, and companies can obtain a better image through advertising that they are environmentally conscious.
The tax scheme did not have the intended outcome with regard to hospitals. The Danish EPA produced a report in 2006 showing that the use of phthalates had fallen in general, except for in the hospital environment21. An increased phthalate tax would decrease the difference in cost even more, thereby reducing the savings obtained by using phthalate-containing products. Hospitals would then, presumably, be motivated to phase out medical devices made of phthalate-softened PVC. On the other hand, there are examples where a phthalate-free procurement policy has not lead to an increase in expenses, even without the phthalate tax. The Hospital Westfriesgasthuis in Holland and the Hospital of Southern Jutland in Denmark are examples of how a conscious procurement policy can replace a large proportion of the phthalate-containing medical devices without an increase in expenses. Still, more economic incentives could get more hospitals to follow their examples.
http://www.ft.dk/samling/20051/almdel/mpu/bilag/343/267804/index.htm
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Glossary Authorisation List The EU’s list of chemicals where companies must seek approval if they wish to continue the production of a chemical on the list or to continue using a listed chemical in an article. Bioaccumulation A continuing accumulation of a chemical in an organism. The specific description for when a chemical, for example a brominated flame retardant, is accumulated in a living organism during its lifetime. If an organism absorbs more that it releases, a bioaccumulation occurs. Bioaccumulation also describes bio concentration, which means that the concentration of an environmental poison increases in a living organism compared to its surroundings (biomagnification), i.e. the accumulation of the toxin can be amplified up through the food chain. Biomonitoring A scientific technique that assesses a person’s exposure to natural and synthetic chemicals. Candidate List The EU’s list of chemicals that are considered particularly problematic. These chemicals have long-term harmful effects on human health or are damaging to the environment. The chemicals on this list are candidates for the authorisation list. The newest version of the list is available here: http://echa.
europa.eu/chem_datAa/authorisation_process/candidate_list_table_en.asp Carcinogen A cancer-causing chemical. Cocktail Effects All the chemicals that occur in a mixture contribute to the overall effect, which the mixture can have on both on humans and the environment. This may be toxic. The chemicals may be harmless to the environment and humans at low concentrations and acting singly, but when combined they can become toxic. Cocktail effects are also called mixture effects and combination effects. Condensation Reaction A chemical reaction where two molecules or functional groups combine to form one molecule while releasing a smaller molecule (often water) Cryptorchidism A condition where the testes have not yet descended into the scrotum at birth. Directive A directive is one of the legislative acts used in the EU. Directives are binding for Member States, which they apply to. Directives must be implemented by the national legislature before they apply. This must occur within a given time frame, often two years. When im-
plemented, the Commission must be informed. ECHA (The European Chemical Agency) The function of this agency is to ensure that the EU chemicals legislation REACH and the Regulation regarding classification, labelling and packaging (CLP) are carried out in a unified manner throughout Europe. Among other things they receive registrations on chemicals. Exposure Means to come into contact with. You can, for example, be exposed/ come into contact with a chemical by inhalation (breathing in) or through the skin (e.g. chemicals in sunscreens etc.) Electrolytes Electrolytes are natural salts in the body fluids and include sodium, calcium, potassium, magnesium, chloride and phosphate. Endotracheal When something is placed in the trachea. (Trachea=windpipe) Epigenetic Is the study of hereditary changes in the expression of genes or the cellular phenotype (what you can see, measure, weigh etc.) which are caused by other mechanisms than changes in the DNA.
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Ester A series of chemical bonds which are created by a chemical reaction between a carboxyl group (-COOH) and an alcohol (a common term for the chemical reaction that has a hydroxyl-group (-OH)) with the removal of a water molecule. Polyester is a category of polymers that includes the ester group in the main chain. Hermaphrodite An animal or plant that has both male and female reproductive organs and is able to reproduce with both sexes. Hemodialysis When waste products and excess fluids are removed from the blood through a filter outside the body. This is in contrast to p-dialysis (peritoneal dialysis) where the blood is cleaned through the peritoneum. Hemolysis Describes the situation where the red blood cells release hemoglobin (and other contents) to the surrounding because the cell membrane is damaged. Intravenous Inside a vein (blood vessel that carries blood to the heart)
In Vitro research Scientific research that is carried out on cells. This is outside the living organism, often in a test tube or a petri dish. In vivo research Scientific research that is carried out on the living organism. This is typically done on animals, but also includes clinical trials on humans. The EU chemicals legislation REACH aims at reducing animal experimentation. Metabolites Intermediates and the products of metabolism. More generally, they are described as breakdown products. Mutagen A mutagen is a chemical that causes mutations. A mutation is a change in the hereditary material (DNA) and changes the gene expression in the individual. For example, after a mutation, some proteins may not be expressed. NOAEL No Observed Adverse Effect Level – The largest concentration or amount of chemical that does not cause any change in morphology, functioning, growth, development or lifespan in the observed organisms under defined conditions of exposure during research.
REACH The European chemicals legislation. The word is an abbreviation of Registration, Evaluation and Authorisation of CHemicals. REACH is a Regulation, which means it is binding in the whole of the EU and countries must abide by it. Countries cannot introduce weaker legislation, but on the other hand, they cannot, as a rule, introduce stronger legislation either. Regulation A regulation is one of the legislative processes used in the EU. Regulations apply to everyone. As soon as a regulation is passed it applies immediately throughout Europe. As opposed to directives they do not need to be implemented by the national legislature in order to apply. Regulations are in themselves binding which means they create rights and responsibilities of the same order as national legislatures.
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AN Educational material about phthalates, their use in medical devices and their harmful effects
This educational material focuses on a highly topical debate about the use of endocrine disrupting phthalates in medical devices. Phthalates are chemicals that are added to PVC to soften it. Among other things they can damage fertility, impair sperm quality and cause behavioral disorders, liver damage, obesity and cancer. Phthalates are especially harmful to pregnant women, children, premature babies and chronically ill patients. Denmark must comply with EU chemicals legislation REACH, and three EU directives concerning medical devices. The directives are currently under revision and will be replaced by regulations. Currently, there are no restrictions on the use of phthalates in medical devices , although it has been known for 30 years that phthalates are released from the devices and absorbed by the body.
The Ecological Council Blegdamsvej 4B DK-2200 Copenhage N
tel: +45 33150977 info@ecocouncil.dk www.ecocouncil.dk
There are many phthalate-free alternatives on the market. There is no reason to continue allowing phthalates and exposing vulnerable patients to medical devices that pose health risks. The educational material consists of a documentary, an educational booklet and a teacher’s manual. The documentary is avaliable on Youtube: Long version: http://goo.gl/VnRJ77 Short version: http://goo.gl/Xg9wp5 The material is well suited to teach topics in physiology, biology, chemistry, ethics, social studies and health care in secondary school/preparatory-school/ high school/sixth form college. It is also relevant as part of the nursing education programme and the medical laboratory technology program (bioanalyst education).