4. Long term and cumulative effects of genetic constructs and living modified organisms

Dear Esteemed Colleagues,

We invite you to contribute to the ongoing forum discussion on the long-term and cumulative effects of genetic constructs and Living Modified Organisms (LMOs). This topic raises important questions about the sustainability, safety, and broader impacts of genetic modifications over time.

Ironically, while the topic is all about long-term effects, time itself is not on our side! We have to  close the discussions on Monday 5 May at 11 a.m. Montreal time. If you are already in the midst of preparing a response to this topic, I want to remind you to please submit it before the deadline. I urge you all to please think about this very important issue in risk assessment and share your ideas.  I trust that my co-moderator and I can count on you to provide your insights and expertise on this topic.

A kind reminder to everyone, I would appreciate if you would be able to share the DOI or URL links when sharing references and resources.

Best regards
Anita Anthonysamy

Esteemed colleagues,

In contribution to discussion I would like to comment on the suggested questions 1:

1. One significant challenge related to the topic at hand and current guidelines and regulatory frameworks might be that, by the time long-term studies are completed, new technologies may have emerged, potentially rendering the initially proposed methodology and/or the living modified organism, under study outdated. Additionally, such studies would require substantial and sustained funding commitments to ensure they are fully completed and not left unfinished midway.

My name is Christoph Then. For my affiliations please see the first round of questions. In the following, I try to answer to the questions raised by the moderator.

Question 1
Long term and cumulative effects can be called a ‘dark matter’ of risk assessment. There is no guidance, no methodology and lack of empirical data that would allow to assess their real impact on biodiversity and human health.

Question 2
There are at least three crucial factors that cause specific challenges:

1. The spatio-temporal dimension: If spatio-temporal control is lacking, the uncertainties of risk assessment will increase and its outcome is not reliable. Risks can only be determined for a certain period of time, but not for open ended evolutionary processes. In this context, the biggest problem are LMOs that can spread, propagate and cross with wild species, intentionally (to transform natural populations directly in the environment) or unintended.

2. The scale and the number of releases: Large numbers and repeated releases over longer periods of time will increase uncertainties. Even if the LMOs can not persist, the environment may show severe impacts e. g. from adaption of pests, pathogens and weeds, changes in the soil or in regard to biodiversity.

3. Changes in the receiving environments: Climate change, changes in agricultural practises or the simultaneous introduction of other LMOs into the same environments will increase uncertainties by potential interactions and cumulative effects.


Question 3
All four questions can be answered with yes.

Question 4
Current practises of risk assessment are focusing on individual events that were tested in isolation on small scale and shot period of time. This approach can not longer be seen as sufficiently reliable. Precaution can only be implemented if spatio-temporal control is established. A guidance that addresses long-term and cumulative effects will be necessary to take into account systemic risks that go beyond the assessment of single events and to establish criteria to reject application for releases and market introduction.

For further information you may also interested in our report Testbiotech (2023) Genetic engineering in agriculture: between high flying expectations
and complex risks The use of genetic engineering in agriculture requires a comprehensive technology assessment.https://www.testbiotech.org/en/publikation/genetic-engineering-agriculture-between-high-flying-expectations-and-complex-risks/

This topic is of growing importance given the increasing diversity and complexity of LMOs being developed and released, including those involving genome editing, synthetic biology, and self-propagating elements. These innovations introduce new layers of temporal and ecological uncertainty into biosafety considerations, particularly when effects may manifest over multiple generations or accumulate across landscapes, populations, or ecological networks.

1. How does this topic potentially pose challenges to existing risk assessment frameworks, guidance, and methodologies? Do solutions exist?
Challenges:
Timeframe limitations in existing assessments
Traditional risk assessments often focus on short- to medium-term impacts. Long-term effects—such as gene flow, epigenetic changes, or ecological shifts—may only emerge over years or decades and are not fully captured by current methodologies.

Cumulative and synergistic effects
Multiple releases of LMOs or genetic constructs (e.g., across different traits, species, or geographies) may result in cumulative impacts on biodiversity, such as progressive erosion of genetic diversity or disruption of trophic interactions.

Ecosystem-level feedback loops
Over time, introduced traits (e.g., pest resistance, reproductive control) may interact with evolving biotic and abiotic factors, leading to unpredictable feedback effects such as resistance development or ecosystem shifts.

Monitoring and baselining gaps
Long-term environmental monitoring systems are often underfunded, underdeveloped, or not mandated. Without robust baselines, it is difficult to detect subtle or delayed biosafety impacts.

Potential Solutions:
Integrate long-term impact modeling into risk assessments using ecological forecasting, agent-based modeling, and evolutionary simulations.

Mandate post-release monitoring (PRM) obligations for commercialized LMOs over extended periods, with clear triggers for reassessment or mitigation.

Develop cumulative impact assessment frameworks, possibly drawing from environmental impact assessment (EIA) methodologies used in conservation or infrastructure planning.

Promote regional collaboration for monitoring and data-sharing on transboundary and long-term effects of LMOs.

Expand and update CBD guidance documents to explicitly address duration, accumulation, and multigenerational effects within risk assessment criteria.

2. What could be the specific challenges related to this issue?
Scientific uncertainty and data scarcity: Limited empirical data on long-term performance and persistence of genetic constructs in complex ecological systems.

Detection of low-probability but high-impact events: Rare but irreversible effects (e.g., extinction of a wild relative, ecosystem collapse) may escape early detection without long-term observation.

Adaptation of organisms and ecosystems: Over time, selective pressures introduced by LMOs may drive unintended evolutionary or ecological responses in target or non-target species.

Institutional limitations: Inadequate regulatory mandates, resources, or technical capacity in many countries to conduct or require long-term follow-up assessments.

3. What are the specific issues concerning this topic?
(i) Potential to cause serious or irreversible adverse effects on biodiversity or human health?
Yes.

Traits that spread via gene flow or are integrated into reproductive or ecological pathways (e.g., insect resistance, gene drives) can alter population structures, reduce genetic diversity, or displace native species.

Accumulated ecological pressure (e.g., continuous selection for resistance traits) could undermine ecosystem resilience or pest control strategies.

Persistent LMOs may interact with sensitive or endemic species, especially in biodiversity hotspots or vulnerable ecosystems.

(ii) Potential for deliberate or accidental introduction into the environment?
Yes.

Many LMOs are designed for environmental release and have already undergone field trials or deployment in open systems (e.g., agriculture, vector control).

Accidental releases remain a concern through containment failure, cross-pollination, or inadvertent movement of propagules (e.g., seeds, spores).

(iii) Potential to disseminate across national borders?
Yes.

Long-term presence increases the likelihood of transboundary movement, whether through natural dispersion (e.g., wind, water, animal vectors) or human-mediated trade.

Genetic constructs introduced into one ecosystem may persist and interact with organisms in another over time, with implications for shared biodiversity and biosafety responsibilities.

(iv) Current or likely commercialization?
Yes.

Several LMOs with potentially persistent or cumulative effects are either already in use or undergoing regulatory review, including:

Herbicide- and pest-resistant crops

Sterile insect technologies

LMOs with stacked traits or multiple event constructs

As genome-edited and synthetic biology organisms enter commercialization pipelines, the scale and duration of exposure is expected to grow.

Ossama AbdelKawy
Egypt National Focal Point for the Cartagena Protocol
Microbiology and Biotechnology Professor, British University in Egypt
Research Professor, Egyptian Atomic Energy Authority
Science Advisor, Egyptian Ministry of Environment

Dear colleagues,

Thank you to the secretariat and the moderator for this discussion. My name is Kumitaa Theva Das, and I've been working on genetic constructs for more than twenty years. I'm also a part of the Genetic Modification Advisory Committee of Malaysia. I would like to contribute to question 1.

There are several types of constructs that might pose challenges in risk assessment due to the dynamics of these systems, and detection, depending on the monitoring in place, including these listed below:
i) Epigenetic or regulatory constructs (like RNAi) which modifies gene expression rather than sequence and may be able to influence development over generations. History of safe use and the risk assessment also may not be able to rely on common databases for amino acids and proteins
ii) Slow-spreading gene drives or daisy chain systems which is designed for containment which might persist across generations. Parts of this were discussed in the last AHTEG on engineered gene drives
iii) Biocontainment systems which typically has a kill switch or auxotroph-type system to prevent persistence. The long-term effectiveness may not be known, especially in the event of mutation accumulation
iv) Protein editors which are self-splicing protein subunits which can modify chemical groups and unusual amino acids. This has only been demonstrated in cells, but could be translated to organisms in the near future and could result in off-targets

This is in agreement with posts #12426 and #12439, particularly regarding emerging technologies and timeframe limitations in the current assessment.

Kumitaa Theva Das
Malaysia

Dear participants,

My name is Luciana Ambrozevicius, I´m a regulator and a risk assessor at the Brazilian Biosafety Commission. Thank you for the opportunity to participate in the on line forum. For the proposed topic “Long term and cumulative effects of genetic constructs and living modified organisms” I would like to make the following considerations regarding the criteria for new topics established in the annex I to decision CP-9/13:

1. How does this topic potentially pose challenges to the existing risk assessment frameworks, guidance and methodologies? Do solutions exist?

I do not see a topic such as “Long term and cumulative effects of genetic constructs and living modified organisms” being a challenge for the existing RA framework. There is experience gained through decades from assessing several traits or events (i.e., different LMO modifications) and the same event multiple times (i.e., repeated assessments of a particular LMO across different contexts), with hundred events approved at different countries, consumed by billions and cultivated in million of hectares. The questions we had 30 years ago about cumulative effects, when the first GM plants were evaluated, was not confirmed by any scientific evidence.

Maybe the challenge is to foster more studies about long tem positive and negative impacts of LMOs on the sustainable use of biodiversity and climate change, but this challenge can’t be solved by a RA guidance.

2. What could be the specific challenges to related to this issue?
3. What are the specific issues concerning this topic?

The topic “Long term and cumulative effects of genetic constructs and living modified organisms” is too broad, no specific challenges can be identified. The Cartagena Annex III already indicates where there is uncertainty regarding the level of risk, it may be addressed by implementing appropriate risk management strategies and/or monitoring the LMO in the receiving environment. A case-by-case RA will determine if the risks are acceptable and if it’s necessary to monitor the risks. I fail to see any value of a guidance regarding this topic.  

In my opinion, in this case the proposed topic does not fulfill the criteria according with the decision CP-9/13 and neither will be an outcome useful for Parties.


Best regards,
Luciana P. Ambrozevicius

Dear colleagues,
My name is Ediner Fuentes-Campos, Deputy Director of Research and Development at the Secretariat of Sciences of Panama. I have been working as a risk assessor at the National Biosafety Commission for GMOs and as a public researcher.

Support the position expressed in post #12448, which indicates that this topic does not represent a significant challenge for existing risk assessment frameworks. The experience gained over decades of evaluating hundreds of events in different countries has generated substantial evidence about the long-term performance of LMOs. The questions raised 30 years ago about cumulative effects have not been corroborated by scientific evidence.
Annex III of the Cartagena Protocol already provides adequate guidance by indicating that when uncertainties exist regarding the level of risk, these can be addressed through appropriate risk management strategies and/or monitoring of the LMO in the receiving environment. The case-by-case approach to risk assessment, as established in the Protocol, remains the most effective method for determining whether risks are acceptable and if monitoring is necessary.

From an evidence-based perspective, it is important to note that numerous scientific studies have systematically evaluated the long-term effects of LMOs, including comprehensive reviews conducted by Nicolia et al. (2014) and the National Academy of Sciences of the United States (2016), which have concluded that existing frameworks have been sufficient to identify and adequately manage potential risks (Nicolia et al., 2014; NAS, 2016).
The case-by-case assessment methodology, as noted by Devos et al. (2016), allows for the consideration of cumulative effects when a plausible mechanism for such effects is identified, without the need to create a new assessment category. This methodological flexibility is precisely the strength of the current approach and allows adaptation to diverse regulatory situations.

Advances in analytical techniques for environmental monitoring, as described by Romeis et al. (2020), provide additional tools that can be implemented within the existing framework to detect possible unanticipated effects. These methodologies allow for more precise assessments without the need to develop new specific guidance (Romeis et al., 2020). Environmental risk assessment follows established scientific principles that are applicable regardless of the organism or technology in question, and the current methodological approach adequately incorporates consideration of long-term effects when relevant to a specific case.

Respectfully,
Ediner Fuentes-Campos

Devos, Y., Gaugitsch, H., Gray, A.J. et al. (2016). Environmental risk assessment of genetically modified plants: challenges and approaches. Environmental Research Letters, 14(7). https://doi.org/10.2903/j.efsa.2016.s0508
National Academies of Sciences, Engineering, and Medicine. 2016. Genetically Engineered Crops: Experiences and Prospects. Washington, DC: The National Academies Press. https://doi.org/10.17226/23395.
Nicolia, A., Manzo, A., Veronesi, F., & Rosellini, D. (2013). An overview of the last 10 years of genetically engineered crop safety research. Critical Reviews in Biotechnology, 34(1), 77–88. https://doi.org/10.3109/07388551.2013.823595
Romeis, J., Collatz, J., Glandorf, D.C.M. et al. (2020). The value of existing regulatory frameworks for the environmental risk assessment of agricultural pest control using gene drives. Environmental Science & Policy, 108, 19-36. https://doi.org/10.1016/j.envsci.2020.02.016

Dear all,

Contributing to the discussion, I would like to share the perspective of what is done in Argentina.

We do not consider that a topic such as “Long-term and cumulative effects of genetic constructs and living modified organisms” poses a challenge to the existing risk assessment framework. There is sufficient accumulated experience and evidence to conclude that addressing this topic is not necessary.

A case-by-case risk assessment will determine whether the risks are acceptable and whether monitoring is required. Uncertainties can be addressed through appropriate risk management strategies and/or monitoring of the LMO in the receiving environment.

Therefore, we do not see the need to develop new specific guidance related to this topic.

Dear Participants,

My name is Christophe Boëte, I am a research scientist at the IRD (Research Institue for Developement) in France, based at the Institute of Evolutionary Science of Montpellier, France. Most of my research deals with the interactions between mosquito and their pathogens, the evaluation of novel approaches against vectors at the ecological and epidemiological levels as well as the aspects related to their acceptability and the related regulation. I was a member of the AHTEG that worked on the additional voluntary guidance materials to support case-by-case risk assessments of living modified organisms containing engineered gene drives.

1. How does this topic potentially pose challenges to the existing risk assessment frameworks, guidance and methodologies? Do solutions exist?

The long term monitoring is a challenging point in risk assessment. To name a few elements, this requires the evaluation of gene flow, the likelihood of gene transfer, the measurement of the ecological impact, as well as an estimation on parasite evolution (including virulence towards non-GE hosts) when GE animals are built to increase their resistance to pathogens) and released.

2. What could be the specific challenges to related to this issue?

Over a long period of time the likelihood of having several GE species (including wild ones) in the same ecosystem might increase, impacting then the associated uncertainties. This would clearly add a layer of complexity for their monitoring and the evaluation of their impact on the ecosystem.

The long term monitoring will have also to deal with biotic or abiotic changes in the environment (such as climate change, ecosystem modification, urbanization...)

3. What are the specific issues concerning this topic?

As said in post #12431, the four questions can be answered in a positive manner.

Best regards,

Christophe Boëte

Good day. I am grateful for the opportunity to contribute to this forum. I work as a researcher in biosafety of genetically modified organisms (GMOs) at the Executive Secretariat of CIBIOGEM (Intersecretarial Commission on Biosafety of Genetically Modified Organisms) in Mexico.
From a comprehensive biosafety perspective—prioritizing the protection of biodiversity, human health, and food sovereignty—and drawing on both national and international scientific evidence as well as Mexico’s concrete experience as a center of origin and genetic diversification of key crops such as maize and cotton, I offer the following considerations:

1. Challenges to Risk Assessment Frameworks and Methodologies
Current regulatory frameworks, based on short-term studies and the principle of substantial equivalence, are inadequate to detect cumulative, synergistic, or multigenerational effects. Multiple studies (Shen et al., 2022; Mesnage et al., 2016, 2017; Kilic & Akay, 2008; Séralini et al., 2013) have documented hepatic, renal, endocrine, immune, and reproductive disruptions in animals after long-term exposure to GM maize or soy.

Chronic exposure to residues of glyphosate and Bt toxins (such as Cry1Ab) has been associated with systemic damage even at sublethal doses (Talyn et al., 2019; Mesnage et al., 2017). Additionally, genome editing technologies may cause off-target effects, large insertions or deletions, and chromosomal rearrangements, as well as unpredictable on-target effects such as epigenetic and transcriptomic changes (Kawall et al., 2020).

In Mexico, per capita maize consumption exceeds 195 kg/year, making chronic exposure risks especially relevant. Glyphosate and AMPA residues have been found in maize-based products—even in those labeled “GMO-free” (González-Ortega et al., 2017). This context calls for long-term studies, multigenerational models, and the use of omics tools for more robust assessments.

2. Specific Challenges Related to LMOs
• Gene flow: Transgene introgression into wild populations of cotton (Wegier et al., 2011) and maize (Quist & Chapela, 2001) has been documented, posing irreversible threats to genetic diversity and traditional knowledge systems.

• Unassessed synergistic interactions between transgenes and agrochemicals: One of the main gaps in risk assessment is the lack of evaluation of combined effects between transgenes and their associated agrochemicals. Mesnage et al. (2016) highlight that transgene-herbicide combinations can produce toxic effects not anticipated when assessed independently. This is particularly concerning in stacked events, where multiple transgenes may interact with each other and with environmental factors, unpredictably altering biological or microbial functions.

• Emergence of superweeds and superpests: In the U.S., over 40 weed species resistant to glyphosate and insect pests such as Helicoverpa zea resistant to Bt have been reported (Bonny, 2016; Tabashnik et al., 2013), increasing dependency on more toxic herbicides and undermining integrated pest management.

• New types of LMOs: Gene drive organisms, GM animals (e.g., for accelerated growth), and genetically modified microorganisms for industrial, environmental, or medical use pose new regulatory challenges due to their potential for replication, mutation, and dissemination. These organisms fall outside current regulatory frameworks focused on GM crops, and urgently require adapted and expanded risk assessment methodologies (Kawall et al., 2020).

3. Specific Problems and Potential for Severe or Irreversible Effects
i) Biodiversity: In Mexico, transgene introgression in native maize and wild cotton populations threatens genetic diversity, agroecological systems (e.g., the milpa), and biocultural ties. Additional documented effects include:
• Increased mortality in Adalia bipunctata larvae exposed to Cry1Ab (Schmidt et al., 2009).
• Impaired navigation and behavior in Apis mellifera due to glyphosate exposure (Talyn et al., 2019).
• Neurotoxicity in amphibians from glufosinate exposure (Lajmanovich et al., 2022).
• Ecological disruptions in plant-insect interactions in wild cotton populations containing Bt and cp4-epsps transgenes (Vázquez-Barrios et al., 2021).

ii) Environmental introduction: Unintended presence of LMOs in GMO-free areas—such as native maize fields or wild cotton populations—has been documented since 2001. Dissemination occurs via seed transport, pollen flow, and lack of effective segregation measures.

iii) Transboundary dissemination: Mexico imports large volumes of GM maize from the U.S. Transgenes have been detected in staple foods (e.g., tortillas, cereals), posing a systemic and transboundary biosafety concern.

iv) Ongoing commercialization: Mexico has cultivated GM cotton and soy since the 1990s and imported GM maize for decades. This has led to cumulative transgene release into critical biocultural ecosystems, resulting in genetic erosion and displacement of heirloom seed varieties.

4. Existing Resources and Needs to Strengthen Risk Assessment
Institutional capacities in Mexico (e.g., CIBIOGEM, CONABIO, INECC, academic and research institutions) must be strengthened through:
• Community and molecular monitoring networks.
• Development of multigenerational risk assessment protocols adapted to national conditions.
• Specialized protocols for LMOs derived from new biotechnologies (e.g., gene drives).
• Public databases on cumulative effects.
• Strengthened territorial biosafety systems in coordination with Indigenous and peasant communities.

Mexico reaffirms its commitment to the precautionary principle and advocates for a contextual, multiscalar, bioculturally relevant, and scientifically robust approach to LMO risk assessment—particularly inclusive of local communities and responsive to emerging challenges.

References:
• Bonny, S. (2016). Genetically modified herbicide-tolerant crops, weeds, and herbicides: overview and impact. Environmental management, 57(1), 31-48. https://doi.org/10.1007/s00267-015-0589-7
• González-Ortega, E., Piñeyro-Nelson, A., Gómez-Hernández, E., Monterrubio-Vázquez, E., Arleo, M., Dávila-Velderrain, J. y Álvarez-Buylla, E. R. (2017). Pervasive presence of transgenes and glyphosate in maize-derived food in Mexico. Agroecology and sustainable food systems, 41(9-10), 1146-1161. https://doi.org/10.1080/21683565.2017.1372841
• Kawall, K., Cotter, J., & Then, C. (2020). Broadening the GMO risk assessment in the EU for genome editing technologies in agriculture. Environmental Sciences Europe, 32(1), 106. https://doi.org/10.1186/s12302-020-00361-2
• Kılıç, A., & Akay, M. T. (2008). A three generation study with genetically modified Bt corn in rats: Biochemical and histopathological investigation. Food and chemical toxicology, 46(3), 1164-1170. https://doi.org/10.1016/j.fct.2007.11.016
• Lajmanovich, R. C., Attademo, A. M., Lener, G., Boccioni, A. P. C., Peltzer, P. M., Martinuzzi, C. S., ... & Repetti, M. R. (2022). Glyphosate and glufosinate ammonium, herbicides commonly used on genetically modified crops, and their interaction with microplastics: Ecotoxicity in anuran tadpoles. Science of The Total Environment, 804, 150177. https://doi.org/10.1016/j.scitotenv.2021.150177
• Mesnage, R., Agapito-Tenfen, S. Z., Vilperte, V., Renney, G., Ward, M., Séralini, G. E., ... & Antoniou, M. N. (2016). An integrated multi-omics analysis of the NK603 Roundup-tolerant GM maize reveals metabolism disturbances caused by the transformation process. Scientific Reports, 6(1), 37855. https://doi.org/10.1038/srep37855
• Mesnage, R., Renney, G., Séralini, G. E., Ward, M., & Antoniou, M. N. (2017). Multiomics reveal non-alcoholic fatty liver disease in rats following chronic exposure to an ultra-low dose of Roundup herbicide. Scientific reports, 7(1), 39328. https://doi.org/10.1038/srep39328
• Quist, D., & Chapela, I. H. (2001). Transgenic DNA introgressed into traditional maize landraces in Oaxaca, Mexico. Nature, 414(6863), 541-543. https://doi.org/10.1038/35107068
• Séralini, G. E., Mesnage, R., Defarge, N., Gress, S., Hennequin, D., Clair, E., ... & De Vendômois, J. S. (2013). Answers to critics: Why there is a long term toxicity due to a Roundup-tolerant genetically modified maize and to a Roundup herbicide. Food and Chemical Toxicology, 53, 476-483. https://doi.org/10.1016/j.fct.2012.11.007
• Shen, C., Yin, X. C., Jiao, B. Y., Li, J., Jia, P., Zhang, X. W., ... & Liu, J. P. (2022). Evaluation of adverse effects/events of genetically modified food consumption: a systematic review of animal and human studies. Environmental Sciences Europe, 34, 1-33. https://doi.org/10.1186/s12302-021-00578-9
• Schmidt, J. E., Braun, C. U., Whitehouse, L. P., & Hilbeck, A. (2009). Effects of activated Bt transgene products (Cry1Ab, Cry3Bb) on immature stages of the ladybird Adalia bipunctata in laboratory ecotoxicity testing. Archives of environmental contamination and toxicology, 56, 221-228. https://doi.org/10.1007/s00244-008-9191-9
• Tabashnik, B. E., Brevault, T., & Carriere, Y. (2013). Insect resistance to Bt crops: Lessons from the first billion acres. Nature Biotechnology, 31(6), 510-521. https://doi.org/10.1038/nbt.2597
• Talyn, B., Lemon, R., Badoella, M., Melchiorre, D., Villalobos, M., Elias, R., ... & Melchiorre, E. (2019). Roundup®, but not Roundup-Ready® corn, increases mortality of Drosophila melanogaster. Toxics, 7(3), 38. https://doi.org/10.3390/toxics7030038
• Vázquez-Barrios, M. E., Castellanos-Moguel, J., & Wegier, A. (2021). Ongoing ecological and evolutionary consequences by the presence of transgenes in a wild cotton population. Scientific Reports, 11, 18987. https://doi.org/10.1038/s41598-021-98489-4
• Wegier, A., PIÑEYRO‐NELSON, A., Alarcón, J., GÁLVEZ‐MARISCAL, A., Álvarez‐Buylla, E. R., & Piñero, D. (2011). Recent long‐distance transgene flow into wild populations conforms to historical patterns of gene flow in cotton (Gossypium hirsutum) at its centre of origin. Molecular ecology, 20(19), 4182-4194. https://doi.org/10.1111/j.1365-294X.2011.05258.x

Posted on behalf of Kamal Kumar Rai, Nepal Indigenous Biodiversity Forum (NIBF), Indigenous Knowledge and Peoples Network Society for Wetland Biodiversity Conservation Nepal
*****
Right based robust collective strategy  and mechanism may require case-by-case, establish a do no harm principle in full and effective participation of Indigenous Peoples, local communities at all with ensuring the Free, Prior and Informed Consent function under customary and biocultural protocols in accordance with the spirit and objectives of the Convention.   

Non-state actors, IPLCs will be more in a fragile zone in the sense of wider the traditional ways of life, livelihoods, traditional occupations, indigenous food and health systems, ways of use of ecosystems, management, socio-culture and economics all interact with various factors in nature for sustainability and survival .  Safety and security of sustainability for survival is seeing challenging, under threats, risks means the human rights of Indigenous Peoples and local communities, women youth and persons with disabilities. The impacts of such invasive technological development and innovations is one the main challenges for human, ecosystem, nature and biodiversity at present. Different factors of LMO, EGD and its implications must assess in proper monitor, minise and management as biosafety measures with appropriate tools and regulations.

IPLCs are always keen to support and share the knowledge systems with do no harm

Thanks with regards
Kamal Kuma Rai
IPLCs

In my view, the topic of long-term and cumulative effects of genetic constructs and LMOs does not meet the criteria set out in decision CP-9/13 for identifying and prioritising specific issues for risk assessment of LMOs. This is because the assessment of potential adverse effects, including long-term and cumulative impacts on human and animal health and the environment, as well as their monitoring, are already comprehensively covered by existing risk assessment guidelines.

I am Dr. Nicolas Defarge, molecular biologist, representative of ENSSER (European Network of Scientists for a Socail and Environmental Responsability)
1. How does this topic potentially pose challenges to the existing risk assessment frameworks, guidance and methodologies?
YES, because long term and cumulative effects are poorly studied hence little data is available since there is no guidance, nor methodology to assess them, inside nor outside of the lab.
Do solutions exist?
YES, multigenerational and transgenerational, as well as long term toxicology studies (e.g. chronic (over 12 months) and life long (2-year feeding studies) in rodents can be carried out, indeed few were, wether by the applicant or independant researchers. These were reviewed in Shen, C., Yin, XC., Jiao, BY. et al. Evaluation of adverse effects/events of genetically modified food consumption: a systematic review of animal and human studies. Environ Sci Eur 34, 8 (2022). https://doi.org/10.1186/s12302-021-00578-9: .
As an example, negative effects such as lower litter weight i and higher pup losses were reported in Cyran et al., 2008 (Cyran N, Gülly C, Handl S et al (2008) Biological effects of transgenic maize NK603xMON810 fed in long term reproduction studies in mice. FiBL, Wien, Pdf: https://www.herbogeminis.com/revista/IMG/pdf/effects_of_transgenic_maize.pdf)

2. What could be the specific challenges to related to this issue?
In addition to those reported in the forum, I would like to add one: The quality of diets in rodent feeding trials is crucial. In Mesnage and Defarge, 2015 (Laboratory Rodent Diets Contain Toxic Levels of Environmental Contaminants: Implications for Regulatory Tests, https://doi.org/10.1371/journal.pone.0128429): In this article, we describe the contamination with environmental pollutants of 13 laboratory rodent diets from 5 continents. Measurements were performed using accredited methodologies. All diets were contaminated with pesticides (1-6 out of 262 measured), heavy metals (2-3 out of 4, mostly lead and cadmium), PCDD/Fs (1-13 out of 17) and PCBs (5-15 out of 18). Out of 22 GMOs tested for, Roundup-tolerant GMOs were the most frequently detected, constituting up to 48% of the diet. The main pesticide detected was Roundup, with residues of glyphosate and AMPA in 9 of the 13 diets, up to 370 ppb. The levels correlated with the amount of Roundup-tolerant GMOs. Toxic effects of these pollutants on liver, neurodevelopment, and reproduction are documented. The sum of the hazard quotients of the pollutants in the diets (an estimator of risk with a threshold of 1) varied from 15.8 to 40.5. Thus the chronic consumption of these diets can be considered at risk. Efforts toward safer diets will improve the reliability of toxicity tests in biomedical research and regulatory toxicology. Taken together, these data may challenge the use of external control groups in regulatory chronic health risk assessments (often called historic data), because differential diet contaminations artificially enhance background effects and hide significant effects. It is thus inappropriate to combine different controls from different experiments within the same laboratory because different batches of the same feed may not be always similarly contaminated over time. Differences in feed constituents between countries may be even more important.
Finally, and outside of the lab, if the aim in to assess the cumulative and long term effects of organisms and products obtained by the tools of modern biotechnology, then monitoring should be performed, and it requires declaration (labeling would be the best option) and detection methods as well as infrastructure and fundings available to carry them out.

3. What are the specific issues concerning this topic?
(i) Is there the potential to cause adverse effects on biodiversity, in particular those that are serious or irreversible, taking into account the urgent need to protect specific aspects of biodiversity, such as an endemic/rare species or a unique habitat or ecosystem, taking into account risks to human health and the value of biological diversity to indigenous peoples and local communities?
YES
(ii) Is there the potential to have an introduction into the environment either deliberately or accidentally?
YES
(iii) Is there the potential to disseminate across national borders?
YES
(iv) Is the LMO already, or are likely to be, commercialized or in use somewhere in the world?
YES
4. Are there existing resources on similar issues that can address this issue or resources that could be adapted to address this need?
NO, since current practises of risk assessment focus on individual events that were tested in isolation on small scale and short period of time. In regard to the precautionary approach, this is far too limited to properly assess Long term and cumulative effects of genetic constructs and living modified organisms.

Warm regards to everyone.

Question 1: How does this topic potentially pose challenges to the existing risk assessment frameworks, guidance and methodologies? Do solutions exist?
Long-term and cumulative effects of genetic constructs and living modified organisms (LMOs) are adequately covered under the risk assessment process of the Cartagena Protocol on Biosafety (CPB). Annex III of the Protocol provides a foundational framework for such assessments, requiring that they be scientifically sound, consider biological diversity of the receiving environment, and include monitoring strategies for post-release. The Annex emphasises that the lack of scientific certainty does not equate to an absence of risk.
However, existing guidance may lack tools to adequately model and monitor multigenerational impacts especially with respect to indirect and cumulative ecological consequences. They may also give insufficient attention to ecosystem-level feedback or evolutionary changes over time. This can be overcome with the use of modelling and simulation tools including ecological and evolutionary models that can predict trait persistence and long-term ecological impacts. Scenario based assessments are valuable when there is uncertainty.
Solutions do exist and are being addressed through capacity building and knowledge sharing efforts. For example, in supporting risk assessment and management initiatives for parties, AUDA-NEPAD has facilitated conversations among regulatory bodies to engage on the issues arround long-term and cumulative effects for consideration and decision making.

Question 2: what could be the specific challenges related to this issue
Specific challenges include uneven capacity building and limited data availability across Parties to the Cartagena Protocol. To effectively manage these risks, it is essential to strengthen technology transfer, technical cooperation, information sharing, and sustained capacity-building initiatives.

Question 3:  What are the specific issues concerning this topic?
i) Is there the potential to cause adverse effects on biodiversity?
Yes, there is potential for adverse effects, such risks can be effectively minimised or avoided by ensuring that these considerations are integrated into the risk assessment process and that appropriate risk management measures are implemented. A case-by-case and context-specific approach is essential, as it allows for the assessment to reflect the ecological realities of the receiving environment, while supporting science-based decision-making
(ii) Is there the potential to have an introduction into the environment either deliberately or accidentally?
Yes, there is a possibility of both deliberate and accidental introduction of LMOs into the environment. However, these risks can be effectively managed through the establishment of competent national authorities, robust monitoring and traceability systems, and well-defined contingency and emergency response plans.

(iii) Is there the potential to disseminate across national borders?
Yes, there is potential for LMOs to disseminate across national borders. Given their transboundary nature, cooperation between national regulatory authorities is critical to ensure compliance with the Advance Informed Agreement (AIA) procedure under the Cartagena Protocol on Biosafety.
Within countries, biosafety authorities should coordinate closely with relevant agencies, including customs, trade, quarantine, and environmental protection bodies, to strengthen oversight of transboundary movement. There is need to build institutional capacities across these sectors to enhance their understanding and ensure effective implementation of biosafety frameworks.

(iv) Is the LMO already, or are likely to be, commercialized or in use somewhere in the world?
Yes, LMOs have been commercialized globally since 1996, with a wide range of genetically modified crops such as maize, soybean, cotton, and canola being cultivated and traded. In addition, there are new LMO products in the pipeline under Research and Development  earmarked for commercialisation.
Question 4: Are there existing resources on similar issues that can address this issue or resources that could be adapted to address this need?
There are several existing resources that can be used or adapted to address this issue. These include guidance developed by FAO, EFSA, WHO, and recent voluntary guidance on LMOs containing engineered gene drives.
1. FAO (2011) Biosafety Resource Book – Post-Release Monitoring Module: offers a foundation for post-market monitoring recommending case-specific monitoring and general surveillance.
2. EFSA Guidance on PMEM (2011): provides practical tools for post-market monitoring, including indicators, baseline data, and stakeholder involvement
3. Additional voluntary guidance materials to support case-by-case risk assessments of living modified organisms containing engineered gene drives: Recommends a case-by-case approach using problem formulation, predictive modelling, and exposure pathway analysis to assess long-term and cross-border impacts
4. WHO Guidance framework for testing of genetically modified mosquitoes, second edition: promotes a phased testing approach, from laboratory to field to collect long term ecological data and supports monitoring after release.

Thank you for this topic,

I think this is important issue that warrants further guidance, particularly in the context of consumption as part of a staple diet, the potential increase scale of LMO applications being released, as well as the rise in stacked traits being cultivated worldwide.

I would thus like to express my support for posts that detail the challenges to RA, including #12493, #12492, #12514 and #12439.

Many thanks
Eva

Dear Participants,

Thank you kindly for your insights and your continued active engagement during the second week of discussions.

Week 2 of the Open-Ended Online Forum is now closed.

The online forum remains open for the Week 3 topics. Kindly refer to the ongoing discussions at https://bch.cbd.int/en/portals/risk-assessment/forum/week-3.

Best regards,

The Secretariat