The Danish Ecological Council and Health Care Without Harm Europe call upon EU to:1.Identify, and phase out endocrine disrupting chemicals (EDCs) in all medical devicesunless there are no substitutes available, in this case EDCs should be clearly labelled andsufficient information should be given to healthcare staff and patients.Medical devices,which contain EDCs should be subject to restrictions or authorisation and phased out ifsafer alternatives are available. Priority should be assigned based on their hazardousproperties and the likelihood of coming into contact with the patient, particularly withvulnerable patient groups, such as infants, children, women of childbearing age andpregnant women.2.Give special attention to phasing out the PVC softening group of chemicals calledphthalates.Phthalates are abundant in PVC based medical devices such as blood bags,tubes, catheters and disposable gloves, primarily in the form of the phthalate di-(2-ethylhexyl)phthalate (DEHP). PVC free alternatives products should be mandatory, unlessthey are no substitutes available for specific uses.3.Demand clinical trials performed on all medical devices to be implanted or used in directconnection with the patient, or to be used as a storage device for substances– such asblood, fluid, electrolytes or nutrition mixtures.4.Prohibit the application of all harmful chemicals in all medical devices– includingchemicals known to have either carcinogenic, mutagenic, reprotoxic (CMR) or endocrinedisrupting effects (as covered in point 1).The review of the Medical Device Directives, 93/42/EØF, 90/385/EØF and 98/79/EF, and thetransition from directives to regulation, is a good opportunity to expand the protective role of thedirectives. The recent high profile cases – the silicone breast implant containing industrial silicone_____________________________________________________________________________________________________

The Danish Ecological Council, Blegdamsvej 4 B, DK 2200 København N. ph: +4533150977.

http://www.ecocouncil.dk/ e-mail: [email protected]

HCWH Europe, 1 Rue de la Pepiniere, B1000 Brussels, Belgium, ph: +49 15253978103,

http://noharm.org/ e-mail: [email protected]

(PIP) and the metal-on-metal (MoM) hip implants shedding microscopic toxic metals into the body– have brought focus on the need for a stricter regulation on medical devices.A critical and somewhat overlooked hazardous group of chemicals allowed in medical devices arephthalates. There are strong indications that phthalates are endocrine disruptors, and EDCs ingeneral interfere with the hormone systems of living creatures, which is potentially verydamaging, as it is our hormones which control many biological functions, including reproductionand metabolism. EDCs have been increasingly linked to a range of health problems includingaltered brain development giving rise to behavioural, cognitive or attention deficit disorders1,2,cancers (particularly including breast, prostate and testicular cancer)3,4, diabetes5, reproductivedisorders6, and impaired fertility7in wildlife and/or humans8.The phthalate DEHP is currently on several warning lists, including the EU candidate list, the EUendocrine disruptor priority list and the SIN 2.0 list produced by Swedish ChemSec. Studies havefound phthalate metabolites in the urine of neonates in intensive units, and phthalates and theirmetabolites in general are found in urine, blood, naval cord blood, semen, breast milk, placentaltissue and amniotic fluid. Medical products containing DEHP have to be labelled, and the use ofDEHP is already prohibited in toys and childcare products in the EU (1999/815/EC). There aremany alternative products available to substitute the phthalate containing devices on the market,and various listings have been made by e.g. the Danish EPA9and HCWH10. An example of analternative plasticizer is SOFT N’ SAFE manufactured by the Danish company Danisco. Thisplasticizer is produced from American castor oil and has no negative toxicological andecotoxicological impact. Another example of an alternative product is phthalate free plasticgranulate from Melitek.

Ishido et al., 2007, Mesencephalic neurodegeneration in the orally administered bisphenol A-caused hyperactive rats. Toxicol Lett., 173:66–72Jurewicz and Hanke, 2011, Exposure to phthalates: Reproductive outcome and children health. A review of epidemiological studies. InternationalJournal of Occupational Medicine and Environmental Health, 24:115-1413]Soto and Sonnenschein, 2010, Environmental causes of cancer: endocrine disruptors as carcinogens. Endocrinology, 6:363-3704Jenkins et al., 2007, Prenatal TCDD exposure predisposes for mammary cancer in rats. Reprod. Toxicol., 23:391-3965Lim et al., 2008, Association of Brominated Flame Retardants with Diabetes and Metabolic Syndrome in the U.S. Population, 2003–2004. DiabetesCare, 31:1802–18076Markey et al., 2005, Long-term effects of fetal exposure to low doses of the xenoestrogen bisphenol-A in the female mouse genital tract. BiolReprod. 72:1344-13517Cohn et al., 2003, DDT and DDE exposure in mothers and time to pregnancy in daughters. Lancet, 361:2205-22068Damstra et al., 2002, Global Assessment of the State-of-the Science of Endocrine Disrupters. WHO/I PCS/EDC/02.2. World HealthOrganization/International Programme on Chemical Safety, Geneva9http://www.eco-forum.dk/medicoartikler/Produktliste.pdf

there is absolute proof that they exert adverse effects as a consequence of an endocrinedisruption mechanism of action. Moreover, the criteria should not be restricted toendpoints covered by existing test methods; such that it should be considered how newknowledge can be easily included when available. Furthermore, it is important to adopthazard-based criteria, which do not include any potency thresholds for the identificationof EDCs. This is because it is the time of exposure rather than the dose that seems to bethe most important with regard to the effects of EDCs. The criteria should apply across allrelevant EU legislation.Re.2At a medical facility there are many modes of exposure to phthalates, such as throughintravenous (IV) administration, enteral nutrition, direct contact, inhalation and dermal.Most at risk is the foetus, the prematurely born and the seriously ill children. They are inthe developing growth phase where hormones play a critical role in the normaldevelopment of the child, including the brain. They also have a less effective blood-brainand blood-testis barriers and have less total body fat, resulting in a higher concentrationof toxins. Studies show that enteral nutrition at the neonate intensive care unit (NICU)results in an exposure to DEHP of 40-140 �g/kg body weight per day, compared to a“normal” daily exposure of 3-30 �g/kg BW/day. Parenteral nutrition at the NICU wasshown to give an exposure of up to 2500 �g/kg BW/day. These numbers clearly show anunacceptably high exposure, and this is only from one exposure route out of many eachday. Another example is exchange transfusion or extracorporeal membrane oxygenation,which has also shown to dramatically increase the serum levels of DEHP in infants11.Chronically ill patients undergoing continual treatment, such as dialysis, are also highlyexposed. It has been known for 30 years that DEHP leaks out of medical devices, and it issuspected of teratogenicity (causing birth defects) and endocrine disruption.Furthermore, animal studies show that exposure to DEHP can damage the liver, kidneys,lungs, and reproductive system, particularly the developing testes of prenatal andneonatal males. Therefore we propose that steps are taken immediately to phase out theapplication of phthalates in medical devices. Numerous alternative products exist, andexperiences from many hospitals, e.g. Westfriesgasthuis in the Netherlands, where thePediatric ward has substituted nearly all PVC/phthalate products, shows that it can bedone in a cost effective manner. In addition, HCWH has made a report of hospitalsphasing out PVC and phthalates12.Within the scope of CE labeling, a special risk analysis and clinical assessment is carriedout for every single medical device. It is only for products which have a so-called

‘increased risk’, such as medical implants, that a clinical trial must be conducted as well.The pre-market authorisation process of medical devices needs to be more stringent, asdoes the post-market surveillance. In order to avoid cases such as the widespread use ofthe breast implants containing industrial-grade silicone (PIP), and metal-on-metal hipimplants, leaching metal micro particles such as cadmium, cobalt and chromium into thebody, all medical devices need to undergo vigorous clinical trials.We call for legislators to go in the direction of the pharmaceutical industry, where moreclinical evidence requirements are needed for approval.90/385/EØF article 1(k) states that clinical data can be sourced from clinicalinvestigation(s) or other studies reported in the scientific literature, of a similar device forwhich equivalence to the device in question can be demonstrated..” This shows a severelack of regulation and is the basis for the hip implant case, where the new hip implantswere not required to undergo clinical trials, as they were deemed sufficiently similar tothe previous plastic/ceramic/metal implants. This loophole in the directive needs to beaddressed in order to assure that all new products undergo clinical trials before releasedonto the market.Re.4Like EDCs, no carcinogenic, mutagenic or reprotoxic chemicals may be used in, or foundto leach from, medical devices. In the previously mentioned case with the metal-on-metalhip implants, cadmium, cobalt and chrome were found to leach from the implants, andcause severe damage to nearby tissue and the whole body.