Activities of the Open-Ended Online Forum (2014-2016)

Dear members of the Online Forum,

Please use this thread to share views, relevant guidance and sources information on “Integrating human health into the environmental risk assessment” taking into account the topics “Nutritionally altered living modified plants” and “LMOs that produce pharmaceutical products” as appropriate.

Thank you,
Manoela

Dear Colleagues:

We thank the opportunity to contribute to this forum. We have a general caveat regarding to add more “boxes” to the guidance: maybe efforts would be more effective if focused in reaching first a consensus on the more general roadmap text, and leave the discussion of additional guidance applicable to specific cases for latter.

Nonetheless, surely the present forum exchange will be of use; therefore please note the following comments coming from our experience in other international fora and the biosafety assessment of this kind of LMOs in Argentina:

LMOs modified for nutritional or health benefits harbors traits that are beneficial to the end consumer, most often consisting on compositional improvements that may be valuable from a human dietary viewpoint but don´t affect much the overall composition of the plant. Therefore they are quite unlikely to pose special considerations for biosafety assessment. LMO fitness is unlikely to be improved, and real world examples of compositional modification are unlikely to affect the interaction of the crop with pests, NTOs or pose any differential or increased risk to the c&su of biodiversity.

The food safety assessment of foods derived from rDNA plants improved for nutritional or health benefits is sufficiently covered by the ad hoc annex of the Codex Plant Guideline, which was developed by a working group which I had the honor of co-chairing as a team with colleagues from Canada and New Zealand. This guidance was endorsed by the Codex Task Force on Foods derived from Biotechnology and finally adopted by the FAO/WHO Codex Commission in 2007. You may note this is quite a short annex: even for food safety assessment the need of specific additional guidance demanded by this kind of products is limited.

Thanks once more to the facilitators and the Secretariat for the opportunity to exchange on this issue. We are also very interested in learning from your practical experiences in performing risk assessments for this kind of LMOs.

Best Regards,
Martin Lema
Argentina

POSTED ON BEHALF OF SWEE LIAN TAN
-----------------------------------------------

In Malaysia, any adverse or negative effects on human health (as well as animal health) have always been considered when assessing risks of LMOs.  Examples of items assessed for risks include toxicity, allergenicity, anti-nutritional properties, effect on gut microflora, etc.

Swee Lian Tan

Dear Collegues

I support Martin Lema position [#7581]. Nutritionally altered LM plants unlikely requires additional environmental biosafety assessment respect to other LMO. Even in the case of modifications of plant metabolic pathways affecting the synthesis of bioactive molecules involved in biotic stress responses and interaction with the environment (phytochemicals, fruit colours, volatiles, root exudates) these would fall within the range of natural variation and eventual adverse effects could be detected during the normal risk assessment process used to exclude unintended effects of LMOs. In addition I agree that the Plant Guideline elaborated by the Codex Task Force on Foods derived from Biotechnology effectively cover all the relevant aspects of food safety assessment of foods derived from rDNA plants improved for nutritional or health benefits.

Concerning the question where and how to incorporate ideas and comments for the specific topics, to start a discussion I propose the following:

1) “Nutritionally altered LM plants can be considered as a case of changes in the expression level of endogenous genes resulting in the alteration of the flux through endogenous metabolic pathways and assessed accordingly.”
A similar note could be associated to lines 529-533, pag32, of the part I of the Roadmap.

2) “Considering human health as the protection goal and the potential receiving environment , the safety assessment of foods derived from LM plants improved for nutritional or health benefits can be conducted according to the Guideline elaborated by the Codex Task Force on Foods derived from Biotechnology”.
A similar note could be associated to bullet (f), lines 575-576, pag 33 of the part I of the Roadmap.

Finally, I suggest that the topic “LMOs that produce pharmaceutical products” should be treated separately from “Nutritionally altered LM plants” as it raises completely different safety concerns, is linked to a different regulation (pharma production and trade) and is mainly intended for confined use.


I thank the moderator for taking this not easy duty.

Best regards,
Simona Baima
Italy

The same situation in our country - any potential adverse effect to human health is always considering before release of LMO even for confined field trials. I`m totally agree that there is a need to point the key concepts of the Risk assessment for human health, but as Francesca said to find where to put it and give the direct references to existing guidelines that provide good examples of risk assessment in this field. E.g. in our country we gave some explanations in the text of our guidance on this topic:
1. When referring to Elements for consideration regarding characterization of the LMO (Equivalent of line 563 of the Guidance “Molecular characteristics of the LMO related to the modification…»)
We noted: There is a need to prove, that inserted sequence corresponds to the sequence which is expected to transform. In case of detection of potential chimerical ORFs the bioinformatics analysis should be done to establish possible similarity with known toxins or allergens.
2. In line equivalent to line 569 «Genotypic and phenotypic changes in the LMO, either intended or  unintended, in comparison with the non-modified recipient, considering those changes that could cause adverse effects. These may include changes in native/endogenous gene expression and  regulation at the transcriptional, translational and post-translational levels».
We noted:  comparative analysis may include the use of databases for molecular genetics and chemical analysis, toxicological and allergenic tests.
And links to the relevant databases coud be given near this element.
3. Then in our Guidance we have short chapter describing principals of the potential toxicity and allergenicity evaluation, based on the FAO and other relevant recommendations. The additional elements that can be taken onboard from this chapter and inserted in the text of this Guidance in addition to the existing elements for consideration where appropriate:
1). The starting point in assessing the safety of LMO plant origin is a comparison of data from LMO and control (e.g., parent organism) on key nutritional and anti-nutritional components, as well as on the levels of toxins.
Kuiper H.A. Safety Evaluation of genetically modified food and animal feed as a basis for market introduction / Report of the Demonstration Programme on Food Safety Evaluation of Genetically Modified Food as a Basis for Market Introduction // Ed. M. Horning, The Hague: Ministry of Economic Affairs, 1998. – P. 7-19.
2). The number of experimental studies to assess potential toxicity, and allergenicity is determined  on an individual basis depending on the product (s)synthesized by transgene (transgene), and should be sufficient  to be statistically significant. In some cases, long-term studies may be required, particularly in relation to potential toxicity. Regarding to protein toxicity of certain LMO precautionary approach should be lower if it is proven that it doesn`t have history of harmful impact on humans and animals.
3). Procedures for LMO toxicity and allergenicity assessment progressing as new information appearing and  modifying by the international expert Council (at FAO and WHO).
Relevant sources of information to evaluate potential toxicity and allergenicity conserning  examples illustrating elements:
Evaluation of allergenicity of genetically modified food [On-line resource] / Report of a Joint FAO/WHO Consultation on Allergenicity of Food Derived From Biotechnology, Rome 22-25 January 2001, 27 p. // Access mode: http://www.who.int/foodsafety/publications/biotech/en/ec_jan2001.pdf, Date of access: 28.07.2014.
Draft guideline for the conduct of food safety assessment of food derived from recombinant DNA plants / Joint FAO/WHO Food Standards Programme «Codex Alimentarius Commission». Appendix II, Twenty-sixth session (ALINORM 03/34). FAO Headquarters, Rome, 30June – 7 July 2003. – P. 47-57.
Safety aspects of genetically modified food of plant origin / Report of Joint FAO/WHO Expert Consultation on Food Derived from Biotechnology // Geneva, Switzerland, 29 May – 2 June 2000. – P. 1-37.
Best wishes, Galina

Dear Francisca, the Secretariat and Online Forum participants

We would like to mention that the Trans-Tasman food regulator – Food Standards Australia and New Zealand (FSANZ) - has issued approvals for food derived from the following nutritionally-altered lines;
- Corn modified to increase the level of lysine. Line LY038 (NZ BCH entry 108344)
- Soyabean modified with RNAi sequence to increase the level of oleic acid. Lines: DP-305423-1 (NZ BCH entry 108410) and MON87705 (NZ BCH entry 108458)
- Soybean modified to produce stearidonic acid. Line MON87769 (NZ BCH entry 108414)
The FSANZ food safety risk assessments can be accessed via the New Zealand BCH Profile. Environmental safety assessment information for some of the cultivated lines can be accessed via ISAAA (the International Service for the Acquisition of Agri-Biotech Applications).

Thanks, Stacy

Dear Francisca, dear colleagues:
I also thank the Secretariat for the opportunity to contribute to this forum and Francisca for moderating it. I agree with previous comments from Martin (#7581) and Boet (#7632) questioning the usefulness of adding more “boxes” to the guidance. As Boet said, this will diminish its flexibility and suggests the guidance is not accomplishing its objective of being relevant for all types of LMOs. Also this effort to provide detailed guidance will be contradictory to the statement on line 162 that says that “the Roadmap introduces basic concepts rather that providing detailed guidance".
I also agree with Martin [#7581], Simona [#7589], Maria [#7625], Andrew [#7630], Boet [#7632] and Thomas [#7633] that the safety assessment of foods derived from rDNA plants improved for nutritional or health benefits is sufficiently covered by the ad hoc annex of the Codex Plant Guideline, developed under Codex Alimentarius, so there is no need for different groups with different mandates to repeat tasks. This is reflected in our national legislation having different authorities (and expertise) evaluating food safety than the ones assessing environmental risks.
 
Also I would like to take the opportunity to propose a clarification on line 534 and 535 when talking about Elements for consideration in Step 1. The Roadmap uses as examples “(i) any toxic sequences that have been inserted into the host organism”. I will propose to clarify that it could be “any sequence inserted in the recipient organism (which the language used in annex III, instead of host) that produces a toxic protein” for example. Sequences are not toxic per se.  Also for (ii) when it says “any endogenous toxic gene could have been upregulated…” I would add “identify any endogenous gene that codes for a toxin, which could have been upregulated as a result of the genetic modification”. Considerations like these if they are clearly written would suffice for considering, in general, modifications about nutrition. Then another element for consideration would be that modifications consisting of compositional improvements that may be valuable from a human dietary viewpoint, don’t often change other aspects of the nutritional composition of the plant. Therefore they are quite unlikely to pose special considerations for environmental risk assessment.

In relation to LMOs that produce pharmaceutical products, I support arguments shared by Maria [#7625], Andrew [#7630], Thomas [#7633] and Laura [#7645].

Dear colleagues, Dear Sol

I disagree with the proposed change to lines 534-535 by the addition of the phrase "that produces a toxic protein”. The use of dsRNA as an insecticide makes clear that toxic effects arise from molecules other than proteins.

With best regards
Jack

Dear colleagues,

Let me briefly support Sol's comments, as well as her support for the previous comments by others on this topic.

Since Sol mentions the "boxes" that have sprung up in the Roadmap, let me voice my view that these boxes are becoming a confusing clutter for the novice risk assessor for whom this Roadmap is intended.  The boxes are becoming a parking place for ideas that the group cannot decide whether they are really relevant to the text.  In some ways, they are becoming an extension of the criticisms that have been leveled at the preceding draft of the Roadmap concerning the lack of explanation about "points to consider".  In written and verbal comments, people have asked me what this really means in practice.  The "points to consider" and accompanying text do not make clear what type of information is really relevant to predict which adverse effects are likely when an LMO interacts with its likely environment(s).  As a consequence, the text and boxes give the impression of endless data sets that might be considered (although whether the information has predictive value is left unstated).  In actual practice, many of the information sets mentioned have little predictive value for an effective risk assessment.  For example, most experienced risk assessors know that the phenotype of the organism (both the LMO and non-LMO version) is of much greater predictive value in a risk assessment, rather than much of the  molecular genetic data, and long list of -omics data that is currently cited. 

In the case of the "boxes" and body of the Roadmap, it is important for the AHTEG to recognize that extraneous and unclear information in the guidance is just as counter-productive in a guidance document as extraneous information is in a dossier under review by a risk assessor when trying to evaluate likely environmental effects.

I realize that this comment is a slight digression from the topic of "integrating human health effects", but I hope the message is useful to the AHTEG for this and other topics as they move forward with their work to meet the mandate from the Parties.

Best regards,

David Heron
Biotechnology Regulatory Services, USDA-APHIS

Dear colleagues,

I support Martin's position with regard to nutritionally altered plants (#7581), that it is quite unlikely that they pose special considerations for the environment since they are specifically developed for nutritional or health benefits.

Regarding the effects on human health of nutritionally altered plants, I would like to stress that,  in the EU regulatory framework, the effects on human health related to the environmental risk assessment of a GM plant relates to possible immediate and/or delayed effects on human health resulting from potential direct and indirect interactions of the GM plant and persons working with, coming into contact with or in the vicinity of the GM plant release(s). Reference to this approach has already been made in the current Guidance Document on Risk Assessment of LMOs (lines 649-650).  Furthermore, in the EU, the risk assessment of GM Food/Feed (including nutritionally altered GM food/feed) is addressed under a separate regulatory framework. Similarly, at international level, the risk assessment of GM food, including nutritionally altered food, is fully addressed by the Codex Alimentarius. 

I therefore believe that the current guidance for the risk assessment of LMOs can cover the risk assessment of nutritionally altered plants without having to add specific information (if any) in the guidance.

With regard to LMOs that produce pharmaceutical products, my comments are similar. The EU regulatory framework on pharmaceuticals requires an environmental risk assessment in case of GMOs that produce pharmaceuticals, but the principles with regard to human health are the same ones described above. Therefore, I do not see what kind of additional information for these LMOs will provide added value to the guidance.

Kind regards,
Maria

Dear Colleagues:
We appreciatte the chance to contribute to the dicussion.  I would like support Martin Lema, Maria and Adrew Roberts's comments. The safety assessment of foods derived from rDNA plants is covered enough by the ad hoc annex of the Codex Plant Guideline (risk assessment of GM Food/Feed), regarding that point there are no reason to include this consideration in the environmental risk assessment. At Mexico the risk assessment of GM Food/Feed is performed for a different competent authority (COFEPRIS) that the environmental risk assessment. In the case of LMOs that produce pharmaceutical compounds, they should not be grouped with nutritionally altered, in fact in our case the pharmaceutical compounds are excluded from the Law for Biosafety and Genetically Modified Organisms (LBGMO) and they are under the Health regulation framework.

Thanks again to the Secretariat and to Francisca for her role in moderating the discussion.

I would echo the comments of Martin Lema (#7581) and Maria Kammenou (#7625) on considerations for human health and for nutritionally altered plants.  Food safety is appropriately addressed through reference to the Codex guidelines and it is very difficult to see how nutritional alteration is specifically relevant for biosafety. 

I agree with Simona Baima's assertion (#7589) that LMOs that produce pharmaceutical compounds should not be grouped with nutritionally altered LMOs.  However, I would go a step further and suggest that categorizing introduced substances based on their eventual use by humans is not particularly helpful to environmental risk assessment of LMOs, although it may be useful to deal with public perception or for administrative purposes.  Keep in mind that many pharmaceutical compounds are derived from plants that are not LMOs, and that the potential for a pharmaceutical compound to cause harm in the environment is not well correlated to its use as a pharmaceutical.  So, the categorization is not particularly useful or relevant for environmental risk assessment.  Beyond stating that introduced substances intended to be used as pharmaceuticals should be assessed for all of the same endpoints as other introduced substances, it is unclear to me what value this might add to the usefulness of the Roadmap.

Thanks for moderating Franseca. This has been a very interesting round of discussion. I would like to fully support Andrew's views and those of Martin. Food safety issues are outside of the scope of the environmental risk assessment and are better dealt with elsewhere. I am struggling to see how there are special issues that would apply to nutritionally enhanced plants and there is extensive experience producing these types of crops through conventional processes, such as the high oleic, low linolenic oil seed crops or low glycine soybeans which hve been produced using conventional breeding.

With regard to pharmaceutical producing plants, in order to meet production standards, maintain security and ensure quality control, I would expect that, as is the case today, pharmaceutical production using plants would take place under controlled contained conditions which is outside the scope of the Roadmap. In addition, as there is very little real experience to draw on, this seems like a very low priority topic where little of value can be added.

Dear all, dear Francisca,
I support Martin Lema (#7581), Maria Kammenou (#7625) and Andrew Roberts (#7630) in their view that taking into account human health in the environmental risk assessment of LMOs does not necessarily mean that their food safety should be assessed. 
As also indicated by Maria, in the EU ‘human health’ is covered by the environmental risk assessment of LMOs by taking into account  potential adverse effects as a consequence of coming into contact with LM plants(parts) and handling plants by workers. Food safety is, and should not be, part of the environmental assessment.
The guidance should be flexible and robust enough to cover all LMOs, including “nutritionally altered living modified plants” and “LMOs that produce pharmaceutical products”.  Adding more and more examples of specific LMOs to the guidance in ‘boxes’ or in additional guidance will not improve its flexibility and even suggests that each LMO needs its own specific risk assessment. This can create confusion for novel risk assessors.

Kind regards,
Boet

Dear all, Dear Franscisca,

By this note, I add my support to the interventions made by Martin [#7581], Simona [#7589], Maria [#7625], Andrew [#7630] and Boet [#7632] who have clearly pointed out that the food safety of an LMO is best assessed under the guidance given by Codex.  References to food safety in the guidance are inappropriate and distracting. 

With regard to LMOs that produce pharmaceutical products, I support ideas shared by Maria [#7625] and Andrew [#7630].   Producing pharmaceuticals in plants is not novel (I believe approx. 80% of all pharmaceuticals are plant-based).  Furthermore, their production and human use is heavily regulated already.  In addition, most business models for LMO-based pharma products (plants, bacteria, yeast) are based on strict contained use.  They would not be subject to transboundary transfer and handling.   Reference to them in the guidance beyond, perhaps, mention that they exist is unnecessary. 

Finally, building on a point made by Andrew [#7630], diverting the guidance to speculate on intended human uses is not particularly useful.  We should ensure that the established fundamental principles of risk assessment are clearly presented in the guidance.  It should be made clear that risk assessment must adequately address uses that trigger concern i.e., production of an environmental toxin that is likely to cause an adverse non-target effect, or creation and release of a probable, invasive organism.   In this way, the risk assessment informs the risk management which is guided by public policy. 

Thanks,
Tom

Dear all,

Regarding the human health I would like to echo Martin Lema [#7581] that the “The food safety assessment of foods derived from rDNA plants improved for nutritional or health benefits is sufficiently covered by the ad hoc annex of the Codex Plant Guideline”.

Best regards,
Luciana
Ministry of Agriculture / Brasil

Thank you all for the interesting discussion on this topic. I hope to make a constructive comment on how to incorporate it better into the Guidance, Part I.

While it can be at times useful to distinguish between a nutritional characteristic and a pharmaceutical, what does unite these different kinds of modifications is that the product is not intended to be substantially equivalent to the parent. This creates potential challenges for traditional comparative risk assessment approaches that, while not insurmountable, do provide a rationale for specific text.

Having reviewed submissions to this forum I see much attention to food and one could easily get the impression that this would be the only potential exposure pathway for human health. Moreover, I get the impression that the adverse effects are being thought of as anti-nutrients or toxins in food when the ERA could/should consider broader scenarios.

Where food is the, or an, exposure pathway, then there may be in many countries a specialist food safety regulator, as Stacey illustrates for Australia/New Zealand. But FSANZ, for example, does not consider exposures that would arise from environmental release, such as alterations that may affect pollen in plants, leading to inhalation and contact exposures. (To my recollection, FSANZ did not even consider requesting data on inhalation exposures from processed flour in the assessment referenced on high oleic acid soybeans. [#7615])

The changes may also either qualitatively or quantitatively alter the ecology of the agroecosystem itself. Pharmaceutical products may also have unintended potent effects on eg vertebrate pests, or may be taken up from pharma animals by blood sucking insects that also visit humans. The latter was considered by the New Zealand environment regulator in an approval to make genetically engineered cattle (GMD02028). In that specific case, the overall risk was determined to be low or manageable, but it was included in the environmental assessment. It is unlikely that it would be considered a relevant risk for a food regulator looking at a steak, or more seriously because it is unlikely that such animals would be approved to enter the food supply and thus never reviewed by a food safety regulator.

Nutritional enhancement of crops may result in increasing the carrying capacity of disease vectors. It is well known that crop pests can flourish during drought, in part because amino acids are more concentrated in plant fluids. Free lysine availability, for example, limits aphid populations (Environmental Entomology, 39(3):856-864. 2010). Thus alterations such as enhanced free lysine accumulation, a limiting amino acid, may under other conditions relieve nutritional limitations on invertebrate or vertebrate crop and human disease vectors.

These seem to me to be legitimate issues for an environmental risk assessment and I am unaware of their coverage by most, or any, specialist food safety regulator or by Codex. The differences between what may be considered by food safety and environmental regulators with regard to this topic could be a useful addition to the Guidance in the form of a text box in the section: Step 1. In addition, relevant risk issues for consideration could be described with links to “Elements for consideration” f-i.

Best regards
Jack

Dear colleagues,
I agree with the majority of the posts on this topic that food safety is covered by assessments under Codex, and generally undertaken by a food safety regulator so does not need specific guidance in the Roadmap.
I would also like to echo the comments by Sol (#7646) that most countries have a regulatory framework where different regulators have expertise and conduct specific assessments on environmental release of LMOs in addition to those conducted on food products, pharmaceutical products or pesticides produced from LMOs.
In a traditional comparative risk assessment the LMO is compared to an unmodified parent plant and the assessment takes into account any altered phenotype due to the production of novel products, thus the general guidance would cover assessment of all the additional exposure routes which might lead to an adverse outcome discussed in post #7639.

Dear all

Thank you for the interesting discussions on this topic.

The Cartagena Protocol clearly obliges Parties to take into account risks to human health. As such, we do not see the addition of text boxes or further information to be included in the Guidance on this topic as unnecessary as stated by some in this forum.

In our view, the intention would not be to duplicate a health risk assessment or a safety assessment carried out in accordance with the Codex Principles and Guidelines, but to provide further information that is relevant to the assessment of the LMO and to fill the gaps where the former processes may have fallen short. This has been amply explained by Jack Heinemann (#7639).

A useful and practical addition to the Guidance would be to also focus on the 'how' aspect of integrating human health into the environmental risk assessment. For example, as stated by several contributors, at the national level, different parts of the regulatory system may have different responsibilities. Ensuring that they speak to each other in a coherent manner and putting in place the modalities by which they can do so is also important.

Kind regards
Lim Li Ching
Third World Network

I apologise for posting on this topic again, but I think it is important to emphasise that this topic is not about food. It is about LMOs that are nutritionally altered plants and LMOs (of any species) that produce pharmaceuticals. Neither of these would have to be intended to be human food to be relevant to human health. The nutritional alteration could be to a type of seaweed not eaten by people and for purposes of feeding fish in a reef. Therefore it is not clear to me how these LMOs would necessarily come to be reviewed by a food regulator. When the nutritionally altered or pharma LMO is used as food, then there is Codex. The Codex could be linked as 'additional guidance' for such topics, but it is not guidance that covers all uses of the LMOs of this kind.
For example, when LM cattle and sheep were made to express pharma compounds in New Zealand, our food regulator did not assess them. Our environment regulator did. The guidance is for the latter.

Best regards
Jack

Dear Forum Participants,

I would like to begin my post by referring back to the statement of the current topic, which relates to "[i]ntegrating human health into the environmental risk assessment” taking into account the topics “Nutritionally altered living modified plants” and “LMOs that produce pharmaceutical products”.

We have heard from a number of regulators on this thread that this subject is dealt with adequately under other safety assessment regulations within their respective countries.  One the other hand, the examples provided to support additional effort on this topic, advanced by Jack Heinemann in posts #7639 and 7654, are either irrelevant to the subject, do not support the necessity for separate guidance, or are speculative:

1)  Pharmaceutical products unintended effects on vertebrate pests:  Since this relates to the health of vertebrate pests, it is not relevant to the issue of integrating human health into environmental risk assessment.
2)  Pharma animals as the source of exposure of pharmaceutical products:  The fact that it was considered by the New Zealand environment regulator shows how such risk can be incorporated into an environmental assessment.  Providing this document as a resource to other regulators should be a sufficient guide to how this is done.  More extensive effort should be unnecessary.
3)  Free lysine (or other elevated nutrients) relieving nutritional limitations on invertebrate pests:  This is not relevant to human health. 
4)  Free lysine (or other elevated nutrients) relieving limitations on human disease vectors:  This is an extrapolation presented without evidence to support plausibility, and therefore is too speculative to justify additional guidance.
5)  Seaweed modified for the purpose of feeding fish in a reef, not human food:  This is not relevant to human health.

Given the list of topics that we and the AHTEG are already dealing with, efforts to increase the proliferation of unnecessary guidance should be avoided, especially since the Roadmap itself has yet to be adopted, placing any subsidiary documents or discussions of shaky ground.  My sense from this thread is that the overwhelming majority (myself included) believe that the subject of integrating human health into an environmental risk assessment is adequately addressed elsewhere, and is not a priority for action at this time.

(Response to 7578) Yes, all risks are speculative and a good risk assessment keeps them that way. The point is that how humans are exposed to nutritionally altered plants or LMOs that produce pharmaceutical products do not have to be via food. In which case, a food regulator would not evaluate them. It would be left for the regulators that may use this Guidance.
The risk pathway may be indirect, such as increasing the population of a vertebrate that is a disease vector, or of an invertebrate that is a disease vector, but that does not make it irrelevant to human health. I think this is precisely the value of developing text on the matter.

Best wishes
Jack

I agree with Jack Heinemann that “Nutritionally altered living modified plants” and “LMOs that produce pharmaceutical products” should remain together in one category in the Guidance because they are both designed to be different to a comparator.  However, for the discussion below, I will at initially deal with them separately on the basis that nutritionally-altered living modified plants are generally designed to come into the food supply (eg golden rice) while LMOs that produce pharmaceutical products (e.g. morphine) are generally designed to be kept out of it, due to possible side-effects of that pharmaceutical product on people who do not need to take it. 

Regarding “Integrating human health into the environmental risk assessment” taking into account the topic “Nutritionally altered living modified plants”:

I disagree with Simona Baima [#7589] when she said “Even in the case of modifications of plant metabolic pathways affecting the synthesis of bioactive molecules involved in biotic stress responses and interaction with the environment (phytochemicals, fruit colours, volatiles, root exudates) these would fall within the range of natural variation and eventual adverse effects could be detected during the normal risk assessment process used to exclude unintended effects of LMOs.”   I disagree because it is the role of the risk assessment process to determine if this is the case rather than to assume that it is the case.  Furthermore, if the LMO was able to produce the nutrient “within the range of natural variation”, then genetically modifying the organism would not be required.

I also disagree with her when she said [#7589] "Nutritionally altered LM plants can be considered as a case of changes in the expression level of endogenous genes resulting in the alteration of the flux through endogenous metabolic pathways and assessed accordingly."  I disagree because it assumes that ALL nutritionally altered plants, now and into the future, are a result of changing the expression of endogenous genes, when that may not be the case.

Because nutrients are biologically-active substances, they are rarely benign.  It is well-known that some organisms may benefit from an increase in a particular nutrient in the environment, while other organisms may be harmed.  Therefore, determining which organisms may benefit and which may be harmed by an environmental release of a nutritionally altered LMO should be part of a risk assessment process.

Nutritionally altering LMOs for human consumption is generally done as a means of supplementing the population with that nutrient, generally because there is a potential public health benefit from doing so.  Therefore, there are really two questions that should be asked: First, is it a good idea to supplement the population with that nutrient?  What are the risks and benefits to human health of doing so?  Only if it is decided, based on the evidence, that the benefits outweigh the risks, then the next question should be asked: is it a good idea to use the LMO to do that?

It is important to realise that while some people may benefit from an increase in a nutrient (usually those who are deficient in it), others may be harmed by it.  This has led to major debates in public health about whether certain foodstuffs (eg bread) should be supplemented with nutrients (eg folate to prevent neural tube defects), because while some may benefit (the foetus of pregnant women who have a low blood folate level), others may be harmed (folate may increase rates of cancer or hasten its progression, and due to its complex interaction with vitamin B12, folate supplementation may worsen cognitive impairment and anaemia in the elderly (Smith, 2007). Furthermore, some nutrients may cause harm during particular parts of the lifecycle of the organism (e.g. vitamin A is a well-known teratogen in a number of species including humans, so should not be consumed by pregnant animals, including women).  In addition, while extra beta-carotene in golden rice may benefit some children, it is well known that beta-carotene increases the risk of lung cancer in smokers (Tanvetyanon and Bepler, 2008). 

The medical and nutritional literature is replete with many such examples and debates.

The people who have considerable content knowledge about the risks and benefits of supplementation like this are Public Health Nutritionists.  Consequently, they are a resource that should be mentioned in the Guidance.  They can often be found as academics in Universities or as members of a Public Health Association in the country doing the assessment.  If there is no such organisation in the country, then such organisations in other countries can be accessed, such as those in the countries of Europe, the USA, Australia etc. 

The organisation known as the Cochrane Community (previously called the Cochrane Collaboration) (http://www.cochrane.org) is an independent body of 37,000 volunteers in 130 countries that collects, reviews and summarises evidence from medical research to assist people (including regulators) to make decisions based on evidence.  In particular, they conduct systematic reviews of randomised controlled trials and publish them in the Cochrane Library.  These reviews include some on dietary supplementation.  Consequently, if a nutritionally altered living modified plant has been altered to increase the concentration of a particular nutrient, the Cochrane Library may act as a resource by providing a suitable independent summary of evidence about the efficacy and risks of supplementation. 

While some countries may have a food regulator who may look at supplementation, the regulator may not use such well-qualified independent sources. 



Regarding “Integrating human health into the environmental risk assessment” taking into account the “LMOs that produce pharmaceutical products”:

I am assuming that this group of LMOs are designed to produce a pharmaceutical product (eg in the tissues of a plant), the LMO is then harvested and processed to obtain the pharmaceutical product, and that product is then refined and purified for use e.g. morphine from LM poppies, or LM corn producing a product to prevent blood from clotting.

Many postulated LMOs are species that are part of the human food supply, such as maize, leading to a risk that they may accidentally enter the food supply via direct contamination or via pollen.  The experience with Starlink corn, Liberty Link rice and Roundup Ready wheat informs us that this is a very real possibility.   

There are therefore three main risks that should be assessed: 
(1) What is the additional risk (if any) of the pharmaceutical product to the expected user because the product has come from a LMO?
(2) What is the risk to the population if the LMO contaminates the food supply?
(3) What is the risk to those that come into contact with the LMO via other means, eg inhaling plant dust when harvesting and processing a LM crop?

The first question is really a question of chemistry, such as are there any other products that the LMO produces that may end-up in the pharmaceutical product, how well the product is purified and how good the quality control is to ensure that the final product is what is expected and that there are no contaminants. In my opinion, that sort of assessment should ideally be done by the pharmaceutical regulator in the country.

The second question relates to the risk of exposing many people to a small dose of the pharmaceutical product via their diet.  The Cochrane Library is good at assessing the risks and benefits of pharmaceutical products, including adverse effects, and hence is a good resource for this purpose

However, some LM plants may be designed to make a precursor to that pharmaceutical product, where, after harvest and purification, the precursor undergoes one or more chemical reactions in a manufacturing plant to change it to the final pharmaceutical product.  If this is the case, in order to properly determine the risk to public health if the substance accidentally enters the human food supply, the product made by the plant should undergo a thorough toxicology assessment of at least 90 days duration so as to provide regulators with sufficient information to be able to do a risk assessment. 

Similarly, whether the LM plant is designed to produce an active pharmaceutical product or a precursor to it, animal experiments should be undertaken to determine its toxicity via dermal and inhalation routes, and regulators should be given such studies.  Most pharmaceuticals are designed to be taken orally or intravenously and may only be assessed for toxicity by the chosen route of administration. 

The nature of the possible harms and the doses at which these may occur will inform whether the LMO could be released into the open, be retained in a more secure facility (eg in a glasshouse) or securely contained in eg a laboratory, whether the LMO’s by-products (eg plant trash) may be fed to farm animals or not, whether the LMO is a risk to native species and the nature of the personal protective equipment (PPE) (if any) that may be required to prevent dermal and inhalation contact by farm and factory workers. For example, a LM crop designed to produce a blood clotting factor or a substance to induce abortions may require substantial PPE during harvesting and processing.

I suspect that a separate section under Part II may be required for nutritionally altered living modified plants and LMOs that produce pharmaceutical products.  Given that nutrients and pharmaceutical products are both biologically active, LM crops with these attributes should be monitored in the environment to determine if their presence affects organisms in the environment, hence they should also be mentioned in Section III Monitoring of living modified organisms released into the environment.

Furthermore, their effects on human health should also be monitored, for those receiving the pharmaceutical product as planned, those with occupational contact with the LMO, and the general community in case the LMO escapes into the food supply, and these forms of monitoring should also be placed in Section III.

I note that there is currently very little in Section III about monitoring for human health.  A paragraph or box could be inserted about how this is generally done by interrogating the health surveillance systems and registries available in different countries.  Different countries have different systems.  Most developed countries have at a minimum, a deaths database where every death and reason for death is recorded, a hospital surveillance system whereby certain information about why a person was admitted to hospital is recorded, what was done to the person (eg the type of operation performed) and the length of stay, a cancer registry where every cancer diagnosis is recorded, as well as various other health surveillance systems (eg for infectious diseases).  

References

Smith AD (2007). Folic acid fortification: the good, the bad and the puzzle of vitamin B-12.  Am J Clin Nutr, 85(1):3-5.  PMID 17209170)

Tanvetyanon T, Bepler G (2008).  Beta-carotene in multivitamins and the possible risk of lung cancer among smokers versus former smokers: a meta-analysis and evaluation of national brands.  Cancer 113(1): 150-7.  PMID 18429004.