Reports & Opinions
The Risks in Medical Technologies
The Scientific Opinions of David F Williams
Written for the EU
The European Dimension to the Scientific Basis of Risk Management
To most non-European citizens, and I suspect to most European citizens as well, the structure and activities of the European Union (EU) are probably very opaque. The EU is the supranational political and economic union of 27 Members States that are located primarily within Europe. It was created in the aftermath of World War II with the objectives of stabilizing a still-fragile continent. It grew in stages from the original six countries (France, Germany, Italy, Netherlands, Belgium and Luxembourg) to 28, and then back to 27 once the UK left the EU in the so-called Brexit deal in 2020. Incidentally, the whole of my activities covered in this section could not have happened if Brexit occurred much earlier.
The European Commission (EC) is part of the Executive of the EU and consists of subject-based departments, known as Directorate-Generals (DGs). It is that part of the EU that formulates laws and regulations, which ultimately have to be approved by the European Parliament. Most of the work of the EC takes place in Brussels, Belgium. It is not surprising that, with up to 27 states, many of which have been in major disputes, and indeed wars, with each other over preceding centuries, agreements over critical issues have often proved elusive, and the structure of the EC has been in constant flux. One area that has witnessed relative harmony over the years has been that of public health, and the management of risks to the health of the citizens of the EU. This has largely been dealt with by one DG, now referred to as DG Sante, which has used a series of Scientific Committees to evaluate risks and advise on the role of legislation in the control of risks; for example the Scientific Committee on Food is responsible for advice on regulations related to food safety.
SCMPMD and SCENIHR
The safety of medical products and drugs has always been an important issue and in the 1990’s, what was then DR Sanco set up a Scientific Committee on Medicinal Products and Medical Devices (SCMPMD). I was appointed to this committee in 1997 and elected Vice-Chair for the period up to 2003. A reorganization of committees then took place and SCMPMD was reconstituted as the Scientific Committee on Emerging and Newly Identified Health Risks, (SCENIHR), not a very elegant title but it served a very useful purpose. I was a member of SCENIHR up to 2007.
These committees included representatives from many member states and would meet, in plenary session, every few months to agree on future agendas and approve or disapprove reports from the various working groups that had been established. Although plenary meetings used simultaneous translation, the working groups used only the English language and since I was the only native English speaker with experience in medical technologies on the main committees, and had a good reputation as a writer and editor, I was usually chosen as the rapporteur, and sometimes also chairman. of working groups.
This was an intense period, and the construction of our reports, officially called ‘Opinions’ took a great deal of background research, careful crafting and then robust defense. By the time SCENIHR was in place, each opinion had to be published as a draft for public consultation and, in a process open to public scrutiny, I had to decide whether to accept other’s opinions and modify the document, or politely refute them. There was a great deal of pressure, applied from two sides; usually industry groups would argue for less control over technologies that carried some risk, while consumer groups (and some very forceful individuals) argued, usually on the basis of the widely promoted ‘precautionary principle’, that no risks were acceptable. On one occasion, after an Opinion that concluded that there was a minor level of risk, which could be easily managed, especially in the context of the significant health benefits, was published, an irate member of the UK parliament contacted my Liverpool office to say that no level of risk was acceptable to his constituents (he was shortly up for re-election). In an even more dramatic case, the head of one major European country, facing a national election, asked me to change my published Opinion, which essentially said that one type of product carried an unacceptable risk and should be removed from the market, because it would likely mean the closure of a factory in his constituency.
When Old Favorites Must Give Way: Dental Amalgams, Catgut Sutures and Latex Products
Some products of medical technology have been in use for decades, often providing very good service, sometimes when there are no acceptable alternatives. The work of the DG Sante Scientific Committees frequently addressed the risk-benefit relationships with such products, often driven by public concerns and the introduction of equivalent or better products.
One of these products was dental amalgam. This material is an alloy consisting of mercury, silver, tin and other metals which could be manipulated at room temperature so that, when placed in a prepared cavity in a tooth would set hard, giving a functional, if not aesthetic, reconstructed tooth. It was the primary tool of the dentist to combat dental caries, being introduced in the 19 th century. Not surprisingly, amalgams were always controversial because mercury was a known toxin under some circumstances; the expression ‘mad as a hatter’ emanated from the mental disturbances seen in the hat-making industry, arising from the use of the liquid metal to give felt hats their appearance. For decades it was argued that the mercury from amalgams was released into the patients over years and gave rise to a number of neurological syndromes. Several problems faced those who argued that amalgam should be banned. First, there was no scientific evidence, including metallurgical and epidemiological evidence, that any clinical condition arose from this exposure. Secondly, until the 1990s there were no suitable alternatives. Also, it should be said, that for those who urged that all dental fillings should be removed from patient’s teeth, the process of drilling out the filling gave rise to much higher mercury levels than those associated with leaving them in place. On the other hand, there was mounting pressure from patient support groups for ‘authoritative opinions’ to declare that amalgam was dangerous and was the cause of many diseases, from multiple sclerosis to Parkinson’s; part of the rationale here was that such an opinion would support legal class actions against the dental products industry. My working group was charged with answering this dilemma; we obtained the advice of several senior dental clinicians and determined that since there were now some widely used, aesthetic alternative restorative material, and since nearly all dental schools in Europe were ceasing even to teach the use of amalgams, the ‘problem’ would soon disappear. Those activist groups were distinctly unhappy, but our solution has resolved the issue.
The second example is that of catgut sutures. Forms of catgut had been used in wound closure for centuries, these being fibers prepared from certain animal tissues. Most commonly sheep intestines provided the source material but some manufacturers used tissues from cows. By the 1980s, several forms of synthetic biodegradable polymeric suture had been developed, such that the need for catgut significantly decreased. However, some surgeons preferred the ease of handling of catgut so the industry continued to keep them available; also several European manufacturers sold these products, which were inexpensively made, to lower- income countries abroad. In the 1980s, Europe, especially the UK, was confronted with an epidemic of bovine spongiform encephalopathy (BSE, commonly referred to as ‘mad cow disease’), a fatal prion disease in cows, which could be transmitted to humans through the ‘consumption’ of bovine products. The UK, and its beef industry, were effectively isolated from the rest of the world, a move that was justified since the human form of BSE is Creutzfeldt-Jakob disease (CJD), a potentially fatal condition. Several parts of the medical products industry, as well as the food sector, were affected; many pharmaceutical products used bovine albumin as a transport agent in drugs. Rather late in the day, concerns were expressed about whether catgut sutures of bovine origin could be the source of infectivity and we were asked for an opinion. This appeared to be a simple decision; there was no clinical need for these sutures, and better synthetic alternatives were readily available. A ban on the use of catgut would have been popular. There was one major problem, which caused me to argue against an outright ban. If such a ban was announced in the public media, there would have been an outcry, and everyone who had had surgical procedures during the last decade or so, would consider themselves at risk of CJD. The logistic challenges of going through clinical records over the country to try to find where the sutures had been used, and in whom they were placed, would have been enormous, and to no avail since there was no cure for someone who had been infected. In other words, massive public chaos with no practical resolution. Instead, I argued that each manufacturer of catgut sutures, who had previously received regulatory approval (through the CE Mark process), should be required to resubmit their risk analysis documents to the relevant authorities. This would result in failure to be re-approved such that they would no longer be allowed to legally market their product. Again, problem solved, without the public being aware that there had been ‘a problem’.
The third example is that of latex. The issue here related to latex products, widely used in medical devices such as surgical gloves and some catheters. These are essentially made of natural rubber, which, because of some proteins they inherently contained, produced allergies in some patients, and especially in some clinical staff, who would be exposed many times a day. The allergic potential of gloves was enhanced by the use of powders which facilitated the process of donning the gloves, but these powders actually enhanced allergenicity. Since a significant number of clinicians become sensitized, this was becoming an enormous problem. However, the latex products were inexpensive and easy to use, while in the 1990s there were no suitable synthetic alternatives. Our committee produced a well-structured scientific report, but it was becoming clear that the huge market potential for alternative materials had encouraged manufacturers to invest, and several alternatives, especially synthetic nitriles, were being made available, at reasonable cost, during this period.
The Health Risks of Nanotechnology
At the beginning of the millennium, one of the most frequently discussed groups of scientific phenomena referred to ‘nanotechnology’. These phenomena were introduced to the world of science by Richard Feynman in 1959, interest in its many facets increasing rapidly over succeeding decades. The relevance to medical technologies is that several diagnostic and therapeutic processes in health care require resolution at the sub-micron level, such that dimensions at a hundredth or a thousandth of a micron become of theoretical and practical importance. However, many substances that contain or emit components at sub-micron size have some well-defined toxicological effects, such that the unregulated marketing and use of so-called ultrafine materials was causing concern. The scientific committees were asked to address a number of relevant aspects, starting with recommendations concerning definitions in nanotechnologies, which SCENIHR published in 2007.
This Opinion developed a conceptual structure for definitions, recognizing the need for an overarching framework based on an analysis of existing definitions in these areas, taking into account the need to avoid the promulgation of unnecessary terms and the requirements that it should be based on sound principles of lexicology. Most of the concepts and behavior patterns seen at the very small dimensions associated with nanotechnology are not new, and can be described by the existing terminology used at larger scales. The framework takes into account a number of key factors. First, the selection of the size limits associated with the prefix ‘nano’ is somewhat arbitrary, and there does not appear to be any sharp change in either toxicokinetic or toxicodynamic properties of substances at any particular size. Secondly, many of the terms used in nanoscience are based on commonly used words such as ‘substance’, ‘matter’ and ‘material’ and terms in nanoscience should not conflict with the general meaning of such words. Thirdly, certain physico-chemical properties of the products of nanotechnologies are anticipated to have a major impact on their behavior in the environment. Fourthly, certain forms of substances that have characteristics with very small dimensions are found naturally in the environment such that exposure of man and other species is inevitable. However, there has been, and will continue to be, a significant increase in the use of manufactured and engineered products of nanotechnologies, and it is this increased production which requires consideration of potential new words and definitions. Finally, with respect to small individual components, as size decreases, it may be necessary to distinguish between different sizes of particles and molecules for a variety of reasons. This does not imply, however, that there is, a priori, any greater toxicological, public health, or environmental health concern associated with any one size range.
Using this framework, two of the most significant words that were defined, were ‘nanoscale’, as a feature characterized by dimensions of the order of 100nm or less, and ‘nanoparticle’, as a discrete entity which has three dimensions of the order of 100nm or less’. I found it particularly fortunate to be involved in the formulation of these basic concepts and definitions. The committees have continued to work on nanotechnology features including a very important Opinion on the appropriateness of existing methodologies to assess the potential risks associated with engineered and adventitious products of nanotechnologies.