Office of Technology Assessment at the German Bundestag

Arnold Sauter

Status and prospects of catalysts and enzyme technology

TAB report no. 046. Berlin 1996, 94 pages

Summary

The use of catalysts, and particularly their biological version (enzymes), has recently been the subject of increased debate in research, technology and environmental policy. While chemical catalysts enjoy a good reputation, particularly as aids in reducing automotive emissions, enzyme technology enjoys the favourable aura of biological and hence natural manufacturing processes. Even sharp critics of genetic engineering regard the use of enzymes as important components in a »soft chemistry« as a possibly acceptable application of gene technology. Overall, both biological and chemical catalysis technology are regarded as pioneering key technologies for sustainable futures, as they make possible the manufacture of innovative products (pharmaceuticals, materials) in addition to opening up other important fields of application in chemical synthesis, e.g. environmental protection and energy transformation, and have great potential for breaking down the boundaries between individual disciplines and between fundamental and applied research. In many cases, however, such judgements are based on rather vague assumptions or long-standing examples. Many of the highly promising (and highly touted) applications still lie very much in the future. This status report gives a summarised review of the status and prospects for catalyst and enzyme technology. It covers the technological, economic, medical and ecological potentials and risks, and identifies a number of challenges in research and promotion policy. A comprehensive and detailed study of the use of enzymes and catalysts, and specifically their potential contribution to a sustainable industrial economy, remains an extremely demanding task for the future.

Economic importance and technological trends: chemical catalysts

Chemical catalysts are used in the manufacture of almost all chemical products. Process innovations in the chemical industry in particular are based essentially on developing or optimising catalysts.

In 1993 the world production of industrial catalysts had a value of c. DEM 12 billion, with the USA accounting for c. DEM 4 billion and Germany and Japan for c. DEM 1.8 billion each.

Catalysts are used in oil refining (c. 20%) and the chemical industry (40%) and in downstream emission control (40%, of which in turn 95% is for automotive catalytic converters). Automotive catalytic converters in particular showed dynamic growth in the Nineties as a result of stricter emission levels and will continue to generate (expected) growth rates of up to 5%. As these involve components of consumer products, market prices and profit margins are far higher than for industrial catalysts. However, it is not the value of output or sales of catalysts but the far greater added value in products manufactured with catalysts that determines the economic importance of this technological area.

Of the three leading nations the USA is particularly strong in the field of petrochemical catalysts, Japan in environmental protection catalysts and Germany in the field of chemical and industrial catalysts. For many years now, the German Ministry of Education and Research (BMBF) has invested c. DEM 10 million a year in catalytic research, and in additional there are specific promotional measures in Bavaria and throughout the EU. Spending by industry can only be roughly estimated, but is about a hundred-fold this sum. The BMBF programme is aimed at initiating interdisciplinary approaches in particularly innovative areas in close consultation with users. The parameters for improvement in catalysts are basically their activity, selectivity, physical stability and toxicity. An important goal of research and development is blending heterogeneous and homogeneous catalysis, e.g. through immobilisation processes. A particularly demanding area is the integration of enzymatic approaches into chemical synthesis, which has and will continue to have decisive importance primarily for enantioselective synthesis. Catalysts for supplying, storing and transporting energy and for utilising low-temperature energy are still largely in the research stage.

Enzymes

The main applications and areas for the use of enzymes are food and drink production (starch industry, dairy products, alcoholic beverages, juices and products for the baking and confectionery industries), detergents and cleaning agents, textile, leather and feed processing, manufacturing laboratory grade chemicals and medical diagnostic and therapeutic processes.

Of the more than 7,000 enzymes estimated to occur in nature, so far only around 100 have industrial relevance. World enzyme production has a total value of DEM 2-3 billion, depending on whether we take the primary value of the enzyme concentrates or the price of the preparations made from them for the user. The rate of growth in recent years has been around 10% and is regarded by the experts as realistic for the future. Again, the value added with the help of enzymes is many times greater than their primary value. The European enzyme industry has a share of c. 70% of world enzyme production and employs around 5,000 people. The undisputed market leader is the Danish company Novo Nordisk A/S, with a world market share of c. 50%.

Important technological trends are uses for enzymes in analysis and diagnostics, which e.g. in the form of PCR techniques have moulded the life sciences generally in recent years and will be used in ecological and food technology, and hygiene and medical biosensor technology. Enzymes also play an essential role in the use of renewable raw materials, where they break down materials and so make them available for further processing.

Gene engineering has central importance for the development of enzyme technology, making it possible to obtain virtually any desired enzyme on any scale, with a high yield and high degree of purity. The use of genetically modified enzymes will lead to an expansion of possible uses, in the long run on even greater number of applications maybe provided by the production of completely »designed« enzymes. While at least in Germany only few enzymes produced by genetic engineering are used in the food sector, their share in detergents is already over 90%, bringing their overall share of technical enzymes to more than 50%.

In the production of fine chemicals, enzymes are only exceptionally used for products on the multi-ton scale, even though growing demand is expected because of the need for enantiomer-pure synthesis. However, there a whole range of barriers to greater use of enzyme technology in the chemical industry, ranging from the excessive specificity and sensitivity of enzymes to problems of process conversion to issues of plant depreciation or the occupational bias of decision-makers. As with conventional chemical catalysts, interdisciplinary cooperation is required.

Health impacts and ecological risks

Chemical catalysts are used primarily in closed industrial production systems, so that toxicological problems with compounds that often contain heavy metals arise mostly in production, commercial use and recycling. An improvement in safety is expected from increased immobilisation of catalysts on substrates, which can also facilitate recycling of compounds which are sometimes very expensive. The only »consumer product« is the automotive platinum catalytic converter. Platinum compounds are toxic and particularly allergenic. Despite years of research, our knowledge about the bioavailability of platinum, which is found in increased concentrations at the side of roads, is still very small, and our current state of knowledge does not permit a toxicological assessment of the increasing pollution.

Increasing use of enzymes creates three main groups of problems: (genetically engineered) production of enzymes, commercial use of enzyme preparations and use in consumer products like detergents and cleaning products, and above all in foods.

Industrial production of enzymes is done with few exceptions through the use of micro-organisms cultured in closed systems. Risks to employees can arise primarily from the micro-organisms or their components and by-products, the enzymes themselves and from culture medium components and production-related hazardous substances. From the point of view of the manufacturers and many scientists, genetically engineered production increases the safety of enzyme production, as so-called GRAS organisms (generally recognised as safe) can be used, while in conventional enzyme production and use, a large number of microbes are used which are much more dubious in toxicological terms. Apart from the fundamental debate over the question of the biological safety of production using genetic technology (which is not limited to enzymes and is accordingly not dealt with in this report), the regulations and standards on using organisms in biotechnology still have a lot of gaps and problems, for example in the question of safety classification of production strains, international harmonisation and supervision and monitoring.

The biggest health problems due to the enzymes themselves in production and particularly in commercial use come from the allergenic potential, although this is not limited to enzymes and is rather a general property of proteins. While the know-how needed for industrial safety measures and the corresponding safety consciousness are usually available in a production context, safety consciousness is often inadequate among users, particularly with new applications, e.g. in textile and leather goods manufacture. A further consideration is that there are far more employees in companies using enzymes than in enzyme production companies. Monitoring proposed safety measures, thorough training for employees involved and monitoring compliance with regulations are all needed. Problems with allergies in agriculture and food processing (e.g. mills) could be further exacerbated in future if industrial enzymes are to be produced in genetically-engineered plants.

Among the consumer products, detergents and foodstuffs are the two main sources of human contact with enzymes through use or consumption. Inhalation of detergent enzymes is minimised through encapsulation in dust-preventing particles and apparently does not pose a health hazard even for allergy sufferers. Skin contact both with detergents containing enzymes and with enzyme-free detergents can cause irritative contact eczema, but allergies in the strict sense have not been observed to date (although they cannot be ruled out with absolute certainty for particularly sensitive population groups). In the case of foodstuffs, the enzymes are ingested orally, which has a much lower sensitising and allergenic effect than inhalation. However, the almost unmanageable number of protein additives in processed foodstuffs means a growing problem with food allergies, and particularly the threat from concealed components not naturally expected in the product. Besides a very few enzyme-specific risks these are the dangers in principle of increasingly artificial foods, requiring measures particularly in food labelling and supervision.

End-of-pipe environmental protection and integrated environmental technologies

The most important use of catalysts in environmental protection in quantitative terms is in end-of-pipe and add-on technologies. Besides end-of-pipe catalysts for converting gaseous emissions in industry, power stations and vehicles, this includes a range of add-on or recycling technologies which, in additional process steps, convert pollutants into useful products. Isolated enzymes are not used in practice in such downstream environmental protection, while intact micro-organisms from waste, sewerage and exhaust air treatment are inevitable. As these always involve (highly complex) mixtures of materials, an increase in the use of enzymes, whose outstanding characteristic is the specific conversion of materials, is currently hardly conceivable.

By definition, catalysts reduce the activation energy required for a chemical reaction and increase the yield of the desired product. Replacing or improving conventional processes by using catalysts or enzymes will spare both raw materials (the starting materials) and energy, while at the same time reducing waste. Even if such measures of process or production integrated environmental protection currently have a relatively insignificant role in quantitative (and hence economic) terms, their future relevance for »softer« chemical production is generally stressed as a prerequisite for a sustainable industrial economy. Enzymes in particular are expected to help develop completely new production strategies using renewable raw materials and replace chemical techniques and agents with biological or biologically tolerable processes and materials.

The most-frequently quoted example of product-integrated environmental protection using enzymes is the detergent sector, the most important non-food application of biocatalysts. The question of the past and future role of enzymes in reducing the quantity of detergent and energy consumption (due to lower laundry temperatures) is unclear and controversial. The ecological balance sheets on detergent enzymes available to date have restricted themselves to comparing conventional and genetic engineering production methods, and there have been no ecological balance sheets which take into consideration alternative products and pathways. Textile, leather and paper manufacture are other application areas in which enzymatic processes can contribute to avoiding the use of chemicals and saving water and energy. Doubt has been expressed about the ecological benefits of feed enzymes to reduce the phosphate content in liquid manure, as this is just a partial solution. It is still too early to assess the potential of enzymes as active ingredients in plant protection as a replacement for chemical pesticides. More important is the use of enzymes in environmental analysis and monitoring, where biosensors have long proved an essential aid and where there is still major potential for development.

Problems in evaluation

Issues of comprehensive ecological evaluation of catalytic and enzymatic processes and products have been virtually ignored to date. If existing processes are being modified it is necessary to analyse and include in calculations all production processes involved, both within production facilities and outside these. Even more complex is the situation where production is only possible or economically viable at all as a result of using catalysts or enzymes. Complete material flow studies and product line analyses including the socio-economic consequences would have to be carried out to arrive at a really adequate ecological balance sheet for the product in question. This is particularly true for the use of enzymes which enable the use of completely new raw materials and often completely new applications as well. The material balance sheet required as a first stage seems theoretically possible, although collecting data would be laborious in most cases. A much more difficult question is drawing up an impact balance sheet, which requires that all relevant impact dimensions must be defined, documented and considered (and possibly quantified as well). The most difficult problem of all is actually evaluating the balance sheets. The concept of sustainability in particular involves a high degree of subjective diversity in criteria, frame conditions and objectives among the various actors.

R&D, innovation, future research

The thrust to date in publicly-financed research into combined projects seems both necessary and useful in the field of catalytic research, with its close relationship with practice. In future more effort should be given to ensuring that the comparatively scarce funds are applied usefully and »catalytically« in areas which are highly innovative or relevant to environmental protection, but where private R&D is inhibited by economic reasons or subject boundaries.

Enantioselective synthesis for drugs or plant protection agents and catalytic processes for energy supply seem to have particular promise. The goal of overcoming subject and methodology boundaries is particularly relevant for increasing the use of enzymatic reactions in chemical production processes. Considerations of enhancing both economic and ecological efficiency give particular importance to processes for immobilising chemical and biological catalysts.

In the various applications of enzyme technology, there are interdependencies with economic trends which show the need for special measures to promote innovative capability. For example, the food sector in Germany, which is the largest user of enzyme technology processes, still has a very diversified structure. Although biotechnology offers a range of techniques which have often been developed in highly-innovative micro-firms and could be customised very precisely and at relatively minor expense for a very wide range of needs, the trend is for R&D to be concentrated in the international food industry groups. Small and medium-sized businesses are not in a position to set up their own R&D capability to keep pace with new standards and consumer demands. If the diversified regional structure of the German food industry is to be preserved to some extent, it will be necessary to support manageable and appropriate research projects and cooperation arrangements.

In toxicological study of chemical catalysts, the focus will have to remain on platinum emission by automotive catalytic converters because of their very widespread use. Where enzyme technology applications are being introduced into companies which have previously had no experience of using biological materials, the protective measures in the work area will have to be thoroughly reviewed and adapted. Particularly sensitive areas are semi-open applications, e.g. in the textile, leather and paper industries or in feed additives in agriculture. It is necessary here to document not only the actual enzymes but also the often non-documented accompanying products and contaminants.

Given that our knowledge about the medical phenomenon of allergy is extremely limited and this form of disease has become a growing health threat in recent years, particularly high demands must be set for consumer protection and precautionary measures in the food sector, where enzymes represent only a tiny fraction of the relevant ingredients and additives. Besides stepping up research into the emergence and diagnosis of allergy, allergenicity and allergen identification, consideration will have to be given to extending labelling requirements: these will have to be comprehensive, given the lack of lower limits for allergens.

Increasing use of genetic engineering processes in food and feed production makes further research on biological safety necessary. The GRAS concept of safety stages and evaluation must be further developed, particularly with respect to toxicity and allergenicity, and further consideration must be given in particular to the use of antibiotic resistance genes. All the aspects reviewed are becoming increasingly urgent because of the growing use of enzymes previously not available, of genetically modified enzymes and (as a future scenario) of designer enzymes.

To give a more informative answer than has been possible in this report to the question what contribution enzymes and catalyst technologies can make to sustainable industrial production methods, comprehensive approaches and techniques of assessment must be developed and applied on the basis of detailed ecological balance sheets. They should be supplemented by greater use of discourse and debate processes, involving lay persons.