Dr. Luke Grocholl, Regulatory Affairs Expert
Flavors & Fragrances
Humans have been manipulating the genes of organisms since we first domesticated dogs 30,000 years ago. Although we have domesticated over 1000 different species of plants since then, the direct manipulation of genes was not possible until the 20th century. In the 1920s, it was discovered that x-rays caused changes in genetic material (mutagenesis)1. Centuries of selective breeding took advantage of traits generated from natural mutations to drive desired characteristics in domesticated crops and animals. Now scientists could intentionally instigate mutations. New traits in crops could be generated quickly rather than by generation after generation of selective breeding.
Radiation-induced mutations and later chemically induced mutations discovered in the 1940s2 produced mutations with the hope that they may result in desired characteristics, but this was an inefficient method. Mutations could be instigated in seeds for example, but those crops needed to be planted, harvested and then examined to determine if any desirable characteristics were developed. Developments in chemical mutagenesis methods, combined with a greater understanding of genetics, began to suggest that more precise, directed methods for changing genes were possible.
Significant advances in the 1990s led to tools which perform directed and controlled manipulation of genes to develop organisms with desired traits . These modern mutagenesis methods; zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and the clustered, regularly interspaced, short, palindromic repeats/CRISPR-associated (CRISPR-Cas9) system offer techniques that impact genes with surgical precision, targeting specific genes to yield desired characteristics.
Although mutagenesis methods date to the 1920s, it was the publication of a landmark paper in 19733 that launched the genetic age by detailing a method to splice genes from one species to another (transgenesis). Within two years of the introduction of transgenesis, scientists, physicians, legal experts, and government regulatory experts gathered at the Alisomar Conference Center to discuss legal, ethical, and regulatory issues. The 1975 Alisomar Conference laid the groundwork for regulatory management of genetically modified organisms.
Before discussing the regulations that impact food and its labeling, it is important to understand some of the nomenclature used for the direct manipulation of genetic material either by transgenesis (introducing genes from one organism into a different organism) or mutagenesis (changing of genes within an organism). The European Union (EU), for example refers to the process as genetic modification (GM) and the organisms impacted as genetically modified organisms (GMOs). The USDA (United States Department of Agriculture) refers to the technology for in vitro manipulation of genetic material as bioengineering (BE). English translations of the Japanese regulations refer to the technology as genetically edited. For consistency, the terms used for this technology will be kept consistent with the regions where they are used.
Despite the scientific evidence demonstrating that consumption of foods developed using GMOs is safe, public opinion called for the labeling of foods made with GM ingredients. EU regulations require GM-labeling of food, and regulations in the US being implemented in 2021 also require declarations on food packaging. Japanese regulatory authorities recently evaluated proposals for mandatory labeling of GM ingredients as well. These labeling and declaration requirements impact all food ingredients including food additives and flavors.
Laws regulating GMOs in Europe date back to 19904 and focused on the control of GM crops. Initially EU regulations were developed to limit the possibility of GM crops being released into the wild. Europe also developed the first law requiring labeling of food made with GMO ingredients in 19975. The current EU GMO food labeling requirement, adopted in 2003 (Regulation (EC) No 1830/20036 ), requires any food sold in the EU which consists of or is produced from GMOs must be labelled as containing genetically modified organisms. It is important to note the regulations impacts only foods made using GM ingredients and not those made using GM-derived processing aids, enzymes, or microorganisms such as GM yeast used in fermentation, for example. This is particularly important to the dairy industry where GM microorganisms are often used in cheese and related products. The EU regulations also exempt GM labeling requirements for animals treated with GM medicines or nutritional supplements. Similarly, animals given GM feed are not considered GMOs.
The EU definition for a GMO is an organism “in which the genetic material has been altered in a way that does not occur naturally by mating and/or natural recombination.”7 The regulatory definition further defines the methods considered for qualifying a GMO as transgenic methods, but exempts organisms developed using mutagenesis . Any food derived from an organism developed using mutagenesis methods are therefore exempt from GM labeling requirements. Some consumer groups and non-governmental organizations (NGOs) challenged this exemption, resulting in a recent EU court finding8 which indicated it should only apply to mutagenesis techniques that “have conventionally been used in a number of applications and have a long safety record.” More specifically, it proposed the mutagenesis using ZFNs, TALENs, and the CRISPR-Cas9 system are genetic modification under the regulation as well as any mutagenesis methods developed after 2001, the year the regulation was adopted. This was reviewed by the European Food Safety Authority (EFSA) which decided against adopting this interpretation of the regulation. As such the EU does not consider species developed using mutagenic methods as GMO, however, under the EU framework, member state may implement local requirements as long as they do not contradict the EU regulations. France and The Netherlands opted to adopt the interpretation of the court ruling, so in these two EU nations, food derived from organisms developed using these mutagenesis methods are subject to GM labeling requirements.
Until recently there were no mandatory bioengineered food labeling laws in the United States. In 2016, a GMO labeling law was enacted by Vermont, creating momentum for a federal labeling law. The Vermont law was then overturned by the federal government pending nationwide regulation. That regulation, USDA regulation 7 CFR 669 (the National Bioengineered Food Disclosure Standard) requires labeling of bioengineered (BE) food or food made with BE ingredients. Implementation began January 1, 2020 with compliance mandatory by January 1, 2022. Under this US regulation, applicable ingredients must have a text disclosure, symbol, or electronic or digital link indicating it is “bioengineered food” or contains “bioengineered food ingredient(s).” Unlike EU regulations, the US regulation exempts material with no detectable genetic material, however, in order to qualify for this exemption, it must be demonstrated the genetic material was removed by a validated process or demonstrate there is no genetic material present in the food by testing.
Japan also regulates the labeling of food that contain genetically edited (GE) ingredients. Japanese regulatory authorities identified eight crops and 33 ingredients from those crops which require GE labeling.10 Where food uses any of the identified ingredients, the food must be labelled as derived from genetically edited crops if the GE-derived ingredient is one of the top three ingredients by weight, or comprises ≥5% of the food by weight. There are non-GE versions of the identified crops and ingredients, therefore, if any ingredients are potentially from the 8 GE crops or the 33 GE ingredients, they must be labeled as GE unless it is demonstrated by both testing and supply chain control they are not GE.
European Union: Declarations required for products made using or derived from transgenic organisms. Recent decisions indicate declarations also required for products derived from organism that were subject to new mutagenesis methods.
USA: Declarations required for products derived from transgenic organisms where genetic material is present in product. If genetic material is not present in products derived from transgenic organisms, evidence showing the absence of genetic materials must be available.
Japan: Declarations are required if any of 33 ingredients from 8 identified genetically engineered crops are present as one of the top 3 ingredients or represent ≥5% of the food. If non-GE alternatives are used at a threshold above these levels, testing and supply chain verification must demonstrate that no GE ingredient is present.
The increasing demand for natural flavors has led to increased usage of botanicals used as raw materials. In addition, advances in agricultural methods, spurred on by GMOs, has made some botanical raw materials the preferred source for flavors. For example, fusel oil, which lends alcoholic, woody, ethereal, and sweet flavors to foods and beverages, is a byproduct of starch or sugars fermentation. Corn, grains, and beet root are typical sources of such starches and sugars, and these raw materials are often from genetically modified crops. Because the EU regulation requires GMO labeling on food produced from GMOs as well as food containing GMOs, those flavors derived from GMO feedstock should be identified with an EU-compliant GMO declaration. Under the pending US regulation, these same flavors do not require a biotechnology declaration since they do not contain genetic material, however, records of analytical testing are required to demonstrate the absence of genetic material. Care should be taken to verify if any GMO/biotechnology sources are used in the manufacture of flavors, in order to meet regulatory labeling requirements.
For business-to-business transactions, labels/declarations are not required, and statements on GMO/biotechnology provided in product dossiers or separate statements meet the regulatory requirements for declaration.
Although the largest impact of biotechnology on the food ingredient industry has been on the raw materials from which ingredients may be extracted or derived, some ingredients are made using GMOs . Aspartame, for example, is made from amino acids and predates GMOs, but is currently manufactured with amino acids produced by genetically modified bacteria in order to optimize yields. There are now several firms that focus on applying GM technology to microorganisms to yield useful fermentation products. Ingredients produced from non-GMO feedstock using GM microorganisms do not require GM labeling providing there are no detectable GM microorganisms in the final food. For example, glucose made from non-GM corn using GM microorganisms does not require GM labeling.
There are already several flavors available from GM microorganisms such as natural beta-bisabolene (a citrus, balsamic, spicy, woody flavor), the natural citrus flavor nootkatone (a grapefruit, citrus, bitter orange flavor), and valencene (an orange, citrus, fruity, juicy, woody flavor) as well as the sweetener Stevia. Natural fragrances such as beta-elemene (an herbal, waxy fragrance), beta-bisabolene (a balsamic, woody fragrance), sandalwood oil, and patchouli oil are also produced using this technology.
A landmark flavor produced using GM yeast is natural vanillin. The cost of natural vanillin is about ten times that of the synthetic, and GM solutions hold the promise to significantly reduce the cost of natural vanillin. The success of biotechnology in producing such valuable and useful flavors and fragrances will surely continue to drive this field. Whether its an economical route to saffron, or the development of new flavors, genetic modification technology will bring many new flavors and fragrances products to the market.