W. Roy
Jackson
,
Eva M.
Campi
and
Milton T. W.
Hearn
*
Centre for Green Chemistry, Monash University, Clayton, Australia. E-mail: milton.hearn@monash.edu; Fax: +61 3 9905 4597; Tel: +61 3 9905 4547
Too often, the public look at how some areas of industrial chemistry were practiced in former decades, or even past centuries, and conclude that it is a cause of many of the current environmental challenges rather than providing innovative solutions to their needs for goods and services globally. Driven by these public concerns and by governmental policies, confusion can exist about what constitutes the social and economic benefits gained from traditional manufacturing practices and the benefits derived from emerging practices generated from advances in green chemistry and engineering. Tension thus occurs between past practices and current opportunities and how new business models can capture the added value implicit to a more sustainable society that is less dependent on the petrochemical industry for its chemical products.
Arising from the global impact of the current megatrends, in many countries, the public are often unsure where developments in chemistry will take them over the next decades. Understandably, their thinking can take them to the dark, hazardous places of the chemical sciences, where product toxicity is high, safety poor and efficacy low. Worldwide, the classical and more recent popular literature is rich in anecdotes, allegories and allusions on what makes ‘good’, and therefore safe chemistry, and what makes ‘bad’, and therefore hazardous chemistry. In English literature, probably no-where has the negative side of chemistry been more obviously differentiated or better embedded in the public consciousness than in the writings of the Bard of Avon, as evident from the Witches Song in Macbeth Act 4 Scene 1:
Double, double toil and trouble;
Fire burn and cauldron bubble.
Fillet of a fenny snake,
In the cauldron boil and bake;
Eye of newt and toe of frog,
Wool of bat and tongue of dog,
Adder's fork and blind-worm's sting,
Lizard's leg and howlet's wing,
For a charm of powerful trouble,
Like a hell-broth boil and bubble.2
Here, as in Romeo and Juliet or several other of his plays, it is apparent that the Bard well understood the meaning of the words “efficacy”, i.e. the power or capacity to produce effects,3 “efficacious” i.e. an ability to produce a desired effect;3 and “toxicity” i.e. a toxic or poisonous quality, especially in relation to its degree or strength.3 Unfortunately for King Duncan in Macbeth, he was the victim of a toxic product made in a chemical reactor of the Middle Ages. If we fast forward 400 years, it is clear that an enormous amount of intellectual and financial capital has been expensed – some members of the public would claim squandered – over the past centuries to create the chemical industries and chemical products and materials that we take for granted today as essential for our comfort, well-being and good health. Yet, how many of the known 55 million plus chemicals and materials that are accessible currently through databases, such as the ACS Chemical Abstract Service (CAS) or related sources, or the 100000 plus chemicals that are the mainstay of the chemical manufacturing industries have been designed at the time of their creation to have enhanced ‘fitness-for-purpose’ efficacy and also to have reduced toxicity? What metrics have been employed to validate that they actually did achieved these targets and did not succumb to becoming just cacophonies in support of the Witches’ Song and additional ingredients to be fed into their toxic cauldron? Although we still have far to go, fortunately for current and, most importantly, future generations solutions can be now found in the concepts and practices of green and sustainable chemistry and its associated engineering, industrial, financial, commercial and public policy implications!
One of the many attributes of green and sustainable chemistry has been its ability over the past twenty five years to productively link many fields of knowledge into a coherent strategy through delivery of specific practical outcomes, drawing in part upon the lessons of the past. In so doing, it has highlighted over the past twenty five years the dichotomy that exists between what chemists, chemical engineers and other specialists can make and what design tools and technologies need to be created and employed in order to manufacture “safe” chemicals.4 The origins of this dichotomy have been recognised for centuries – one has only to examine the history of poisons from the time of the Roman Empire or even before – to appreciate why tensions have long existed. On the one hand, an enormous level of know-how now exists for individuals to make chemical products by the so-called “make what you can” scenario. In many cases, adoption of this scenario has resulted in processes that require high energy consumption, lead to high waste generation, at times employ highly hazardous procedures. Usually this scenario leads to chemical products being made innocently, but in some other cases, quite deliberately, with little regard to toxicity. Nevertheless, this scenario has come to dominate many different stages of industrial development over the centuries, and frequently this has been carried out with little initial regard for their environmental consequences. On the other hand, the ability increasingly exists for skilled practitioners to deliberately first de novo design and then manufacture commercially important chemical products with improved functional efficacy and toxicity profiles with reduced potential for harm at a defined level of exposure. The longer term eco-environmental sustainability and human well-being benefits of this second scenario are obvious, since these developments can increasingly be based on pathways that involve much more efficient resource utilisation.
To achieve the desired outcomes from this second scenario, sets of guidances are needed. Different facets of these guidances have existed for millennia, with examples found in the clay tablets of the ancient Babylonians, the Papyrus Ebers of ancient Egypt, in texts written by apothecaries working in Bagdad, Spain and elsewhere in Europe during the Middle Ages, all the way up to current times where they can be found inter alia in the extensive published literature released by government regulatory agencies in all industrialised countries. Despite an increasing interest by many educators to promote awareness by chemistry students and more broadly the public of the importance of these guidances and their relevance to a more sustainable society (the C&S programme at Carnegie Mellon University and the ACS On-line Educational Resources for Green Chemistry & Engineering are just two examples),5,6 generally, this literature does not form part of the essential prescribed reading in the chemistry curriculum of schools or universities and hence its full impact has not materialised in the past. However, all of these guidances address common issues related to how to limit the attributional burdens associated with the making of chemical products and the consequential burdens that may affect the environment or human health due to the decision to make and use the chemical product.
The most useful guidances have captured both retrospective and prospective thinking on how to make ‘safe’ chemical products with the desired functionality. In this context, the Anastas–Warner 12 Principles of Green Chemistry7 (Fig. 1) have come to represent a powerful and coherent set of rubrics that link these concepts into holistic frameworks and suggest fields of research, methods of industrial translation and avenues for commercial development where practice can be better aligned with future needs of the public in terms of the creation and manufacture of chemical products and materials that are more efficacious and with lower toxicity. In this manner, efficacy and safety can be integrated into every facet of the chemical product knowledge related to discovery, development, manufacture and end-use within resource utilisation supply-chains.
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Fig. 1 The 12 Principles of Green Chemistry.7 |
Over the past twenty five years numerous examples have been reported where such outcomes have been shown to not only be highly feasible, but also increasingly have proven to be more productive and profitable. They also assuage any fears that the public may have that the majority of chemical products by definition are inherently toxic, whilst their manufacture or use will inevitably lead to risks to human safety or the environment and need to be included in toxics release data, such as an expanded TRI Explorer.8 Moreover, it is now apparent that the deployment of these green and sustainable chemistry approaches to optimise compound efficacy and reduce toxicity are equally relevant to fields within medicinal chemistry as they are to agricultural chemistry, food chemistry and many other industrial and public policy sectors that are dependent on advances in the chemical sciences. With greater confluence of databases, the similarity of this knowledge base will become even more apparent. It is thus not surprising that in recent years increasing interest, both at the academic research level and the industrial deployment level, has been being focused on the application of green toxicology to better guide numerous areas of application, ranging from organic synthesis and medicinal chemistry9,10 to the rational design of chemicals with reduced human or aquatic toxicity.11,12 Linked to these developments has also been the emergence of various roadmaps13 to indicate how better outcomes in the choice of chemical products in terms of their human health risk assessments can be made. Because of these and related developments it is now possible to place a sharper focus on what differentiates the properties of a compound in terms of its human toxicity and environmental toxicity.
As apparent from the growth of recent literature in the field (refer to citations 14–17 for exemplars), it can be anticipated that over the next few years, much greater efforts will be expended by academic and industrial researchers to better formalise property-base approaches and design rules for the synthesis of safer chemicals, not only for use as new medicines but more broadly across all sectors of the chemical industry. These approaches will depend on a variety of computational, free energy prediction, and automated high throughput ex vivo (DNA array, proteomic/metabolic profiling, etc.), in vitro (cell inhibition, proliferation or signalling pathway assays, etc.) and associated in vivo methods of evaluation.
One important area within the field of medicinal chemistry that has particularly benefited from consolidation into a coherent framework of the concepts of how to increase efficacy and reduced toxicity has been the increasing practice to modify the pharmacokinetic and adverse side effects/toxicological profiles of certain drugs through conjugation with benign biodegradable carriers. For example, methods have been developed18,19 to modify the anti-cancer taxane-related drug, paclitaxel, to reduce its toxic side effects, but preserve its efficacy by conjugating it to albumin, biodegradable polyglutamate polymers or to specific monoclonal antibodies, leading to improved health outcomes for women with metastatic breast cancer. The pegylation of recombinant protein biopharmaceuticals, such as α-interferon for treatment of acute Hepatitis C20–22 or the ribosome-inactivating protein, α-momorcharin obtained from Momordica charantia, aka bitter melon,23 for the treatment of human breast cancer are other well-known example where drug delivery and efficacy have been increased and toxic side effects reduced. Clearly, with pharmaceutical products great attention is placed on the possible attributional and consequential burdens of toxicity that a newly made lead compound may have with any adverse effect rigorously determined by preclinical and Phase I to Phase IV investigations required by regulatory agencies worldwide.
Developments that link new technologies to simultaneously increased product efficacy and reduced toxicity are not just reserved to the field of medicinal chemistry. The development of the natural product based insecticides, such as spinetoram,24 derived from the fermentation broth of the soil actinomycete, Saccharopolyspora spinosa (Mertz & Yoa) has led to new avenues to control infestations of numerous chewing insect species by disruption of the acetylcholine neurotransmission in the insect. Further, replacement of some traditional agricultural insecticides in crop protection by the commercial product, Isoclast™, a low molecular weight compound which contains a novel sulfoximine core, developed by scientists at Dow AgroSciences LLC, offers an alternative avenue to control sap-feeding insect pests which are resistant to other insecticides.25 These and similar types of ‘green’ agri-chemicals have a high efficacy because of their minimal impact on beneficial insects but a broad insect pest spectrum, a favourable mammalian toxicological profile, and a lower application rate, particularly for the protection of grain products, leading to minimal environmental impact.26
As far as consumer products are concerned, many examples now also exist where refinements in manufacturing practices or the introduction of new science based on green chemical principles has led to greatly improved “fit-for-purpose” efficacy functions, reduced toxicity and lower environmental burdens. For example, enzymatic glucosylation of polyphenols, such as caffeic acid or epigallocatechin-3-gallate, yield products with preserved or improved antioxidant activity, and generally reduced toxicity. These technologies thus provide access to modified polyphenols with improved properties better suited for use as food additives and cosmetics.27 Similarly, the development by BASF of a high-performance alternative to phosphate (which will be prohibited by the European Union from 2017) in dishwashing detergents involves a biodegradable metal-chelating agent, Trilon® M,28 which is claimed to have improved cleaning power. The replacement of the toxic compound, ethylene glycol, by the food industry compliant propylene glycol is a further example where the previous attributional burden of toxicity has been reduced in applications requiring an antifreeze ingredient without significantly affecting efficacy.29
Finally, in areas associated with the production of bulk and fine chemicals made at large industrial scales, the ‘Presidential Green Chemistry Awards’,30 administered by the United States Environmental Protection Agency, as well as similar awards made in other countries, have been important catalysts for industry to make chemical products of equivalent or improved functional efficacy but with lower attributional or consequential burdens of toxicity or hazard. The recipients of these awards (refer to citation 29 for representative exemplars) have been recognised because the technologies they pioneered, particularly in the fields of biotechnology, polymer science and chemical catalysis with safer chemical feed stocks derived from renewable resources, strongly emphasised process capabilities that drew upon multi-disciplinary research and development teams.
It is clear that much progress has been achieved over the past twenty five years, so green chemists have good reason to celebrate a Silver Jubilee. However, it is also clear that much has yet to be done. If the commitment and passion of the past two decades can be maintained, then we can have confidence that the fundamentals that underpin chemical product efficacy and toxicity at the molecular level will be teased out and much better understood. In so doing, the lid of Pandora's box of toxic compounds will be closed and the imagery, too often held by the public that chemistry is more about products from a Witch’s cauldron than about products that are designed and made to be safe and efficacious, banished to the past. If this occurs, then the public at large will be able to better benefit from access to manufactured chemicals and related products that have their origin in the concepts and practices of green and sustainable chemistry.
This journal is © The Royal Society of Chemistry 2016 |