GMO-db: Comprehensive database on biotechnology products

Biotechnology products

Official detection methods for genetically modified foods

Official Guidelines

Information regarding GMO regulation in various countries

Novel Plant Breeding Technology (next generation genetically modifying technology)

Genome editing technology

Development status of genome edited crops

Information regarding genome edited foods regulation in various countries

Standards for the Safety Assessment of Genetically Modified Foods

Definitions:Recombinant DNA technique

Principles and basic concepts for safety assessment of genetically modified foods (seed plants)

Risk assessment of genetically modified crops

Allergenicity assessment of biotechnology products

Risk communication of biotechnology products

What is genome editing technology?

Document for risk communication of genetically modified foods and genome edited foods (Basic)

Document for risk communication of genetically modified foods and genome edited foods (Intermediate)

Biotechnology products

Official detection methods for genetically modified foods

　“Genetically modified organism” is an organism made by extracting a gene having the necessary characteristic from an organism and incorporating that gene into another organism (plant, animal) to which modification is desired. Because recombinant DNA technology is used in the process, an organism having a targeted characteristic can be made in a short period of time, different from the case of traditional cross breeding. A food using an organism made by using recombinant DNA technology, or part of that organism, is a genetically modified food (A food under Food Sanitation Act. Standards for additives etc. Announcement #370 by the Ministry of Health and Welfare. Food under Paragraph 1. Item 2 of Compositional Standards of Food in general.).
　While the methods to change genome DNA sequence artificially include those using radiation or chemical substance, they are not treated as “genetically modified food” as they do not use recombinant DNA technology.

Biotechnology products that have NOT undergone safety assessment

Biotechnology products, such as foods produced by recombinant DNA technologies, must undergo safety assessment. Products that have not undergone the assessment are called “unauthorized products", which means they cannot be distributed in Japan.
Monitoring inspections for these products are performed at the quarantine offices based on the monitoring plan.

• About foods produced by recombinant DNA technologies
• About official detection
• Information on primers/probes and sequences to be used in official detection methods

Biotechnology products that have undergone safety assessment

Biotechnlogy products for which safety assessment have been completed in Japan. Therefore, they can be distributed by displaying to that effect correctly.

• Detection methods for authorized biotechnology products
• Information on primers/probes and sequences to be used in official detection methods

New labeling system for genetically modified foods will effect on take effect on April 1, 2023.

• pamphlet (Japanese only)

Official Guidelines

Codex guidelines

ISO International Standard

EU-JRC Scientific and Technical Reports

Information regarding GMO regulation in various countries

USA

In the US, there is no law directly regulating genetically modified organism (GMO). In the case of plant, US Department of Agriculture (USDA) makes judgment as to whether a plant is applicable to plant pest or not according to the Plant Protection Act (PPA) (7CFR 340.2 (ref. Document 1)). In the case of food, it is recommended to consult with Food and Drug Administration (FDA) in advance. In the case of animal, the one of which gene has been modified is applicable to animal drug, and therefore, reviewed by FDA (ref. Document 2). In 2015, the Obama Administration made a framework of regulation for the biotechnology products to better fit the modern era (clarified roles and responsibilities of the three related organizations, USDA, FDA and EPA (Environmental Protection Agency)). Through the discussion and analysis by biotechnology working group (USDA, FDA and EPA) and NASEM (National Academies of Sciences, Engineering, and Medicine), the Trump Administration published Executive Order 13874 (Modernizing the Regulatory Framework for Agricultural Biotechnology Products) in 2019 (ref. Document 5).
Based on the National Bioengineered Food Disclosure Law, USDA to established the national mandatory standard for disclosing foods that are or may be bioengineered (7CFR66 (ref. Document 6)). The AMS (Agriculture Marketing Service) in USDA developed the list of bioengineered foods to identify the crops or foods that are available in a bioengineered form throughout the world and for which regulated entities must maintain records. The implementation date of the Standard is January 1, 2020. The mandatory compliance date is January 1, 2022.

（Document 1）7CFR340

（Document 2）FDA 2017draft

（Document 3）2017coordinated Framework

（Document 4）National Strategy for Modernizing the Regulatory System for Biotechnology Products

（Document 5）Executive Order 13874

（Document 6）7CFR66

Europe

In Europe, several genetically modified crops have been approved, and all foods using recombinant DNA technology must be so labeled (Directive 2001/18/EC). Although labeling (indicating GM free) is obligated even for the food in which such technology is not detected or cannot be traced, it cannot be scientifically validated that the food is actually GM free.

（1） EU

• EU-Directive 2001-18 (Original version) (Consolidated version（2019.7.26）)
• EU-Regulation-1829-2003 (Original version)(Consolidated version（2008.4.10）
• EU-Regulation-503-2013 (pdf)
• EU-Regulation-2283-2015 (pdf)

（2） Germany, Austria

• Austrian GM Act (pdf)
• German Genetic Engineering Act (pdf)

（3） UK

• UK-Genetically modified food regulations 2004 (pdf)
• UK-Genetically modified feed regulations 2004 (pdf)

（4） Australia

• Gene Technology Act-2000 (pdf)
• Gene Technology Regulations-2001 (pdf)

（5） New Zealand

• Hazardous Substances and New Organisms Act 1996 (pdf)

Novel Plant Breeding Technology (next generation genetically modifying technology)

　Novel plant breeding technology (abbreviated as NPBT or NBT) is a newly emerged plant breeding technology. It has already been reported in newspapers as the genetically modifying method which leaves no trace. Conventional genetically modified crops have been made by separating a foreign gene from an organism, incorporating such gene into a vector, and transfecting the vector into a cell, in order to make a superior trait express. At this time, only the gene indicating the desired trait is selected among the ones randomly inserted on the genome. The crop obtained this way is a transgenic crop, and the food using this crop has been used after going through the safety evaluation. Around 2010, new recombination technologies made rapid progress. As a result, JRC in Europe summarized then current situation in a report as the “Novel Plant Breeding Techniques” based on scientific literature, patent information and development status. Several countries issued scientific reports.

（Document 1） EU Joint Research Center (JRC)

• New plant breeding techniques－　（pdf）

（Document 2） UK Advisory Committee on Releases to the Environment（ACRE）

ACRE gives statutory advice to ministers on the risks to human health and the environment from the release of genetically modified organisms (GMOs).

• ACRE Report-1 Evidence-based-regulatory-system-for-GMO（pdf）
• ACRE Report-2 Genomes-and-GM-regulation（pdf）
• ACRE Report-3 More-effective-approach-GMO-regulation（pdf）

（Document 3） France Haut Conseil des biotechnologies (HCB)

Set up by the Genetically Modified Organisms Act (GMO Act) of 25 June 2008, the High Council for Biotechnology is an independent body whose role is to inform public decision-making.

• HCB-Scientific Opinion on new plant breeding techniques（pdf）

（Document 4） Australia & New Zealand FSANZ

Food Standards Australia New Zealand (FSANZ) is a statutory authority in the Australian Government Health portfolio. FSANZ develops food standards for Australia and New Zealand.

• FSANZ workshop-New Plant Breeding Techniques（pdf）

Regulatory framework to NBT

• Regulatory framework to NBT (pdf)

Genome editing technology

Major technologies used for development of biotechnology products（pdf）

(1) Radiation, chemical substance
A method where a desired trait is obtained by selection during breeding process after introducing mutation by irradiating gamma ray, such as ⁶⁰Co, or processing with mutagenic substance, such as EMS (ethylmethane sulfonate) or ENU (ethyl-nitrosourea).

(2) Recombinant DNA technology
A method where a foreign gene (sequence derived from soil bacteria or virus) is introduced to add a new trait (such as disease resistance or pest resistance) to conventional varieties. As a gene introduction method, agrobacterium method is mainly used.

(3) Genome editing technology

1. What is “genome”?
   Entire genetic information consisting of a set of DNA held in an organism.
2. What is “genome editing technology”?
   Suppose “genome editing technology” is defined as a “technology to modify a gene using artificial restriction enzyme”, it will become possible to control various mutation (deletion, insertion or substitution of nucleic-acid base, or methylation of a specific base) or expression of a gene at a desired location (targeted site) on a genome of an organism using this technology.
3. Specific examples of genome editing technologies
   Examples include ZFN (Zinc Finger Nuclease), TALEN (Transcriptional Activator-Like Effector Nuclease), CRISPR/Cas (Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR Associated Protein), and currently a system of CRISPR/Cas, which is convenient to use, is mostly used. In case activeness is weak with CRISPR/Cas, or it is difficult to access to the target site, there is a tendency to use TALEN or ZFN.
4. Handling of food made by application of genome editing technology
   Pharmaceutical Affairs and Food Sanitation Council, Subcommittee on Genetically Modified Food and Committee on Novel Foods released a report. According to the report, safety assessment is not required for food made by deletion of a few bases (substitution or insertion etc.) as long as the vector sequences used do not remain.

Development status of genome edited crops.

Information regarding genome edited foods regulation in various countries

Japan

• Guidelines for the handling of genome editing technology applied foods and additives under Food Sanitation Act (pdf) (Japanese only)
• Pamphlet (pdf) (Japanese only)

USA

• Movement of Certain Genetically Engineered Organisms (7CFR330,340,372)
• Plant and Animal Biotechnology Innovation Action PLan (pdf)
• The consultation results of genome edited crops by USDA-APHIS

Europe

• Case C-528/16

The Court of Justice of the European Union decided that organisms obtained by the new techniques of directed mutagenesis are genetically modified organisms (GMOs), within the meaning of the Directive 2001/18/EC on the release of genetically modified organisms into the environment

• A Scientific Perspective on the organisms obtained by the new techniques of directed mutagenesis are subjected Regulatory Status of Products Derived from Gene Editing and the Implications for the GMO Directive

Statement by the Group of Chief Scientific Advisors in European Commission on products derived from Gene editing

• Detection of food and feed plant products obtained by new mutagenesis techniques

Report about detection method for genome edited crops by the European Network of GMO Laboratories

• The EFSA (European Food Safety Authority) evaluation on the existing guidelines for genetically modified organisms (Synthetic Biology, Gene Drive, SDN-1,2,ODM, SDN-3)

New Zealand

• Hazardous Substances and New Organisms (Organisms Not Genetically Modified) Regulations 1998

Standards for the Safety Assessment of Genetically Modified Foods (Seed Plants)

Definitions: Recombinant DNA techniques

　Technique that recombinant DNA molecules prepared by cleavage and recombination of DNA using enzymes or other methods are transferred to living cells for proliferation (the term refers to the techniques that overcome natural physiological reproductive or recombinant barriers and that are not techniques used in traditional breeding and selection).

Principles and basic concepts for safety assessment of genetically modified foods (seed plants)

As for genetically modified foods (seed plants), not only their direct harmful effects on human health but also the nutritional consequences of their long-term consumption should be considered in their safety assessment.
　Most foods that we eat today are known to be substantially harmless during our long history of use, or to become harmless when cooked or processed. For the foods obtained through traditional breeding techniques, toxicological or nutritional testing has not been required because we know from experience that, in most cases, breeding does not cause significant changes in traits that may affect the human health. In general, applying traditional toxicological tests using animals for risk assessment to whole foods is not common due to their great technical difficulties. Meanwhile, safety has not necessarily been confirmed for every component in food. Therefore, the safety or the absence of significant adverse health effects of most foods has been confirmed through their empirical uses as whole foods.
　Also in the safety assessment of genetically modified foods (seed plants), it is difficult to scientifically confirm the safety of each component. Currently, it is therefore reasonable to conduct safety assessment by comparison of genetically modified foods with conventional foods regarding the traits that have been intentionally or unintentionally added or eliminated. Unintended changes are not limited to recombinant DNA techniques but are also associated with traditional breeding. However, the evaluation and prediction of these unintended changes are important in the safety assessment of genetically modified (recombinants) plants as food. For the new technologies without a long history of safe use, potential risks of inducing drastic changes in harmful components or newly generating toxic proteins through the unintended changes in traits should be excluded beforehand as much as possible.
　Safety assessment is feasible only when changes in the properties of genetically modified food (seed plants) are scientifically predictable from the properties of the inserted DNA (gene) and the changes in the modified genome, and when sufficient comparison can be conducted between the host and recombinant plants.

With the above-mentioned principles, safety assessment should be conducted based on the following basic concepts.

1. The safety assessment of genetically modified foods (seed plants) is feasible only when they can be compared with hosts or conventional varieties with a long history of use as foods, or existing foods. This is based on the considerations that safety on the existing traits, aside from those that have been added by genetic modifications, has been widely accepted and requires no further assessments, or that sufficient findings for their assessment has already been accumulated.

2. The most critical elements to be considered in safety assessment are the effects on human health of the traits that have been intentionally added, altered or eliminated through recombinant-DNA techniques, and of the risks such as the production of new harmful components and changes in major nutrients. Furthermore, where recombinant-DNA techniques have been used to intentionally develop the recombinant plants with altered contents of nutrients, functional components or harmful components, the safety of these modifications on human health should be confirmed considering the contents and consumption of such components in other foods.

3. The safety assessment of genetically modified foods (seed plants) is conducted in terms of all changes in the traits expected to be added to the seed plants. For instance, inserting a DNA sequence not only confers a specific trait to the plant (intended effect) but also may also confer additional traits or eliminate or modify the existing traits of the host (unintended effects). These unintended effects may be harmful, beneficial or neither harmful nor beneficial to the growth of the host plant or for the safety aspects of the genetically modified foods. Nevertheless, the effects of the intended and unintended addition of traits or changes in traits should be individually assessed from toxicological and nutritional viewpoints, while the assessment of the safety of the foods should also be conducted from the global viewpoint. For this safety assessment, sufficient data or information should be available to minimize the risk of unpredicted adverse effects on human health caused by genetically modified foods (seed plants).

4. For genetically modified foods (seed plants), the potential effects of food processing, including home cooking, should also be considered. For example, alterations could occur in the heat stability of an endogenous toxicant or the bioavailability of an important nutrient after processing. Therefore, information should be provided on the processing conditions used in the production from the plant and changes in the food ingredients. For example, in the case of vegetable oil, information should be provided on the extraction process and any subsequent purifying steps.

5. Some recombinant plants may exhibit traits (e.g. herbicide tolerance) which may indirectly cause accumulation of pesticide residues, altered metabolites of such residues, toxic metabolites, contaminants, or other substances which may be relevant to human health. These possibilities should also be considered in the safety assessment.

6. In the safety assessment, all the edible parts of the seed plant should be considered. For example, in products such as rapeseed oil, the extracted material from the recombinant plant is usually consumed, but other parts may also be eaten. In such cases, safety assessment of the recombinant plant itself should be conducted considering these points.

7. Studies intended to obtain data for safety assessment should be designed and conducted with sound scientific concepts and principles, as well as, where appropriate, Good Laboratory Practice (GLP). Raw data should be submitted upon request. Data or information necessary for safety assessment, such as experimental data obtained by the developers, published scientific papers and information provided by third parties, should be obtained using sound scientific methods and analyzed by using appropriate statistical methods. Wherever possible, the sensitivity of all analytical methods should be documented.

8. For the safety assessment, it may be required to isolate the novel substance produced in the recombinant plant, or to synthesize or produce the substance from an alternative source. In this case, the material should be shown to be biochemically, structurally, and functionally equivalent to that produced in the recombinant plant.

9. The safety assessment of the currently used antibiotic resistance markers such as the kanamycin-resistance gene has been appropriately conducted, and there have been no safety concerns to date. However, in future developments, alternative transformation methods that do not result in any residual antibiotic resistance genes in food should be considered to be used, where such techniques are available and demonstrated to be safe.

10. Along with the continuing progress in the recombinant DNA technology, these standards should be revised as required.

January 29, 2004 Food Safety Committee decision

Extracted from the safety assessment standards of genetically modified foods (seed plants)

Risk assessment of genetically modified crops

（Nat. Biotech, 26, 73 (2008)）

　The Codex Alimentarius Commission, under the FAO and the WHO, adopted guidelines in 2003 to harmonize the premarket risk assessment process for plants derived from biotechnology (GM plants) in the global market1. The guidelines were approved by the Codex Commission and are intended to guide countries in adopting consistent rules that provide a strong food safety evaluation process while avoiding trade barriers. Each new GM crop requires a premarket safety assessment to evaluate intended and unintended changes that might have adverse human health consequences caused by the transfer of the DNA (genes). The goal is to identify hazards, if found, to require risk assessment and, where appropriate, to develop a risk management strategy (e.g., do not approve, approve with labeling and/or monitoring, or approve without restriction).

　The process is based on the science and requires the use of methods and criteria that are demonstrated to be predictive. New methods should be validated and demonstrated to enhance the safety assessment.

　The framework to guide evaluation of potential safety issues requires detailed characteristics of:

• The GM plant and its use as food
• The source of the gene
• The inserted DNA and flanking DNA at the insertion site
• The expressed substances (e.g., proteins and any new metabolites that result from the new gene product)
• The potential toxicity and antinutritional properties of new proteins or metabolites
• The introduced protein compared with those known to cause celiac disease if the DNA is from wheat, barley, rye, oats or related grains
• The introduced protein for potential allergenicity
• Key endogenous nutrients and antinutrients including toxins and allergens for potential increases for specific host plants (DNA recipients)

Certain steps in the assessment require scientific assessment of existing information; others require experiments, in which case assay validation, sensitivity and auditable documentation are required.

Allergenicity assessment of biotechnology products

　In genetically modified foods, evaluation of allergenicity is significant from the viewpoint of risk assessment. The important points of the assessment are the allergenicity of a gene product newly introduced by the recombinant DNA technology and quantitative change of the inherent allergen protein. The Food Safety Commission of Japan implements allergenicity assessment of genetically modified foods.

Principles of risk assessment of genetically modified foods (The Food Safety Commission of Japan)

Assessment requirement (starting point):
Can be compared with existing food before recombination, and the difference is clear.
　　↓
Because it is difficult to evaluate food safety for each ingredient,
- Compare with existing food and focus on the differences.
- Evaluate the safety of all changes in properties that are expected to be added by recombinant DNA technology, including the possibility.
　　↓
Approve the use as food if it is as safe as the existing food.

(Information exchange meeting between consumer groups and the Food Safety Commission (10th), November 13, 2015) Document 5 (Japanese only)

Outline of standards for risk assessment of genetically modified foods (The Food Safety Commission of Japan)

See Food Safety Commission website for details Link

• Host

(1) Any findings regarding the allergenicity of the host used for developing the recombinant foods should be reported.
(2) If there are any differences in the allergenic components between the recombinant and the host, the influence of such differences on allergenicity should be reviewed.

• Inserted genes

If any open reading frame that can express an unintended protein has been identified, check the allergenicity of the protein (using allergen database).

• Gene product (protein)

The safety of the gene product should be confirmed through reviewing the following (1) to (5).
(1) Allergenicity of the donor of the introduced gene
(2) Allergenicity of the gene product (protein)
(3) Sensitivity of the gene product (protein) to physicochemical treatments

① Acidic and enzymatic (pepsin) treatment with artificial gastric fluid
② Alkaline and enzymatic (pancreatin) treatment with artificial intestinal fluid
③ Heat treatment under similar conditions to those used for usual cooking or processing of foods.

(4) Similarity of amino acid sequence of the gene product (protein) with known allergens (using allergen database)
(5) IgE-binding activity of the gene product (protein)

If the safety of the gene product on human health cannot be confirmed by items (1) to (4), the IgE-binding activity of the gene product (protein) should be assessed. The sera of allergic patients to be used should be selected according to the following ① to ④.

① In cases where the donor of the introduced gene has allergenicity, sera with high titers of donor-specific IgE should be used.
② In cases where the gene product has sequence homology with a known allergen, sera with high titers of IgE specific for the organism bearing the allergen should be used.
③ If ① and ② do not apply, sera with high titers of IgE specific for an organism closely related to the gene donor should be used.
④ In cases where appropriate sera for ① to ③ are not available, sera with high titers of IgE specific for major food allergens (egg, milk, soy bean, wheat, buckwheat, shrimp, peanut, etc.) should be used.

Allergenicity prediction method using the allergen database

As a method for predicting allergenicity of a novel gene product (protein), homology comparison with a known allergen protein proposed by FAO/WHO is used internationally as a standard method. Several allergen databases have been developed that can predict allergenicity by this method.

• FAO/WHO allergenicity prediction method

Homology comparison with amino acid sequences of known allergen proteins, and allergenicity criteria:
(1) 35% or more identity for 80 amino acid segments
(2) Exact match of 6-8 consecutive amino acid sequences

Evaluation of Allergenicity of Genetically Modified Foods, Report of a Joint FAO/WHO Expert Consultation on Allergenicity of Foods Derived from Biotechnology, 22 – 25 January 2001 Link

• Databases capable of implementing FAO/WHO allergenicity prediction method

ADFS: Allergen Database for Food Safety（Division of Biochemistry, National Institute of Health Sciences） ADFS

Allergen Online (The Food Allergy Research and Resource Program (FARRP), University of Nebraska–Lincoln) Allergen Online

COMPARE: the Comprehensive Protein Allergen Resource (HESI, the Health and Environmental Sciences Institute) COMPARE

SDAP: Structural Database of Allergenic Proteins (The University of Texas Medical Branch) SDAP

Allermatch (Wageningen University & Research) Allermatch

International guidelines for allergenicity evaluation method

The allergenicity evaluation method for genetically modified foods has been discussed and guidelines have been proposed by international organizations. The standards for risk assessment of the Food Safety Commission of Japan are established considering the contents of the international guidelines.

Guidelines for allergenicity risk assessment of genetically modified foods

1. Assessment of the allergenic potential of foods derived from genetically engineered crop plants in Crit Rev Food Sci Nutr. 1996;36 Suppl:S165-86, by ILSI Allergy and Immunology Institute with International Food Biotechnology Council (IFBC) USA.(PubMed)
2. Evaluation of allergenicity of genetically modified foods. Report of a joint FAO/WHO expert consultation on allergenicity of foods derived from biotechnology. (Food and Agriculture Organization of the United Nations (FAO), Rome, , 22 – 25 January, 2001.(pdf)
3. Codex Alimentarius Commission. Alinorm 03/34: Joint FAO/WHO Food Standard Program, Codex Alimentarius Commission, Twenty-Fifth Session, Rome, 30 June–5 July, 2003.
   Report of the 3rd session of the CODEX ad hoc Intergovernmental Task Force on Foods Derived from Biotechnology, Yokohama, Japan, 4-8 March 2002.(pdf)

About weight of evidence

ESFA Scientific Opinion
Guidance on the use of the weight of evidence approach in scientific assessments

Risk communication of biotechnology products

What is genome editing technology?

Japanese only

Document for risk communication of genetically modified foods and genome edited foods (Basic)

Japanese only

Japanese only