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The Codex Alimentarius Commission guidelines developed and adopted by the World Trade Organization WTO countries describe an integrated approach for the assessment of the safety of proteins expressed in plants derived from recombinant DNA technology Codex, In general, the food safety assessment is conducted in terms of changes imparted to the host plant, including those resulting from the newly introduced trait intended effect and the potential for modification of existing traits unintended effects.

Proteins are one of the three major nutrient types ingested by humans and animals. Here we focus on the safety assessment of introduced proteins to determine whether they have the potential to exert adverse effects. This paper does not discuss allergenicity, as multiple comprehensive reviews cover this topic EFSA, a ; Goodman et al.

The safety assessment of small RNA molecules Parrott et al. Building on these earlier reviews, we now address the following topics: 1 additional considerations for what constitutes a HOSU for proteins; 2 the effects of food processing on the function and integrity of introduced proteins, and thus on dietary exposure; 3 the potential utility of applying the threshold of toxicological concern TTC concept for proteins; 4 an assessment of the potential for harmful interactions between introduced proteins in combined-trait agricultural crops; and 5 an assessment of whether genotoxicity assays with introduced proteins are needed to confirm their safety on an ad hoc basis.

In Tier 1, no in vivo toxicology testing is considered necessary if the protein meets all of the following criteria: 1 there is a HOSU of the protein or related proteins in foods; 2 the protein is not structurally or functionally related to proteins considered to be toxic or allergenic to humans or animals; 3 the protein has a molecular or biological function that raises no safety concerns; and 4 the protein is readily digested in validated in vitro digestive tests.

If potential safety issues are raised during the Tier 1 assessment, or if assurance of safety is not possible due to limited available information, then additional safety testing, such as acute or repeat-dose in vivo toxicity studies, may be indicated for Tier 2 safety assessment. Safety concerns have been raised about various proteins that have been introduced into GM crops.

Some argue that since proteins introduced into GM crops to control insect pests have been modified from those found in nature e. Bacillus thuringiensis derived Cry insect control proteins these changes may cause unknown health consequences in those who consume the crop. Thus, the GM crops should be subjected to chronic toxicity testing in animals as is done for pesticidal chemicals applied to agricultural crops Seralini et al. In a different publication, Bt Cry insect control proteins have been reported to cause hematotoxicity in mice when Bt microbial spore preparations containing various Cry proteins were administered by stomach tube to mice Mezzomo et al.

Others have reported that administration of Cry proteins to mice by various routes stomach, rectum, nasal or by intraperitoneal injection caused immunogenic effects Moreno-Fierros et al. There were similar reports of immunogenic effects in rats fed Bt rice containing Cry1Ab protein Kroghsbo et al. Regarding the food safety implications of modifying proteins, the genes from bacteria encoding for introduced proteins e.

Bacillus thuringiensis Cry proteins must be modified slightly to facilitate translation of the genes in plants. Modifications of proteins may also be done to enhance their functional activity, but as will be discussed later, such changes are highly unlikely to make a non-toxic protein toxic. There are also fundamental differences in the biological properties of proteins compared to smaller molecular weight chemicals, e.

Hematotoxic effects have not been reported in the many animal studies with Cry proteins and Bt crops following repeated dietary exposures as discussed later.

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Indeed the reported hematologic effects Mezzomo et al. The authors used distilled water instead of Bt spores lacking the Cry genes as the negative control. The Bt spores contain many other bacterial proteins that could have confounded the study results. Doses of Cry proteins reported to cause immunogenic effects in mice were often many thousands of times higher than potential human dietary exposure, and used routes of exposure that were not relevant to dietary exposure intranasal, intraperitoneal injection, etc. Immunogenic responses to proteins that are considered foreign to the species tested are normal responses.

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However, the predictive value of immune findings in mice to humans has not been generally accepted as no animal models are considered validated for predicting immune responses in humans Codex, ; Goodman et al. Some of the results of other studies Moreno-Fierros et al.

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The authors of the repeat study attributed the immunogenic effects observed in the original studies to possible contamination of test articles with endotoxins that can cause immunogenic effects in mice Adel-Patient et al. It would be helpful to summarize some of the key considerations on protein safety from the prior literature, including the ILSI publication Delaney et al. Some of these considerations also address the aforementioned safety concerns. Proteins are fundamentally different from low-molecular-weight chemicals because they are very large macromolecules composed of amino acids.

In the gastrointestinal tract, protein macromolecules, unlike low-molecular-weight chemicals, are subject to degradation by digestive enzymes into individual amino acids and small peptides that can be absorbed by the body to support nutritional needs. In general, the propensity for systemic absorption of any orally consumed substance is inversely proportional to the size of the molecule, with smaller molecules more readily absorbed intact than larger ones Gardner, As such, the potential for systemic absorption of a protein from the digestive tract as an intact molecule is very much less than that of low-molecular-weight chemicals.

These barriers reduce the likelihood that an ingested protein can access critical intracellular spaces such as the cytoplasm and nucleus to impact cellular physiology or DNA integrity. As noted in point 1, the normal fate of most dietary proteins is digestion into peptides and amino acids that are subsequently absorbed into the body Caspary, For a protein to be absorbed intact into the systemic circulation, it would first need to survive the proteolytic environment of the stomach, which is highly acidic and contains multiple proteases.

Plasma membrane lipid bilayers of the digestive tract epithelium are effectively impermeable to exogenous proteins in the absence of specialized membrane transporters that facilitate uptake of specific proteins, although infants on colostrum readily absorb protein nutrients Gardner, These biological barriers generally limit the amount of intact protein that enters the body. Proteins found in living organisms have been isolated, characterized, and assigned to different functional classes having related structures and functions. Despite the large number of known proteins, only a small number are known to elicit adverse effects in vertebrates following oral intake Delaney et al.

Toxicology testing of proteins is recommended in cases where the weight of evidence regarding safety following Tier 1 assessment is considered to be either incomplete or inconclusive. Subsequent testing should be hypothesis based to resolve specific safety questions. Because proteins known to be toxic to mammals and other organisms generally work through specific mechanisms to cause adverse acute effects, testing can often be performed using acute toxicity tests Delaney et al.

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For example, Bacillus thuringiensis Bt -based Cry insect-control proteins work through acute mechanisms to control target insect pests. Candidate proteins intended for use in new GM crops are chosen to avoid potentially adverse consequences. In the unlikely scenario that an introduced protein has a biochemical function similar to a known anti-nutrient proteins found in plants, such as lectins or protease inhibitors, then an acute toxicity study may be insufficient to assess potential toxicity.

These anti-nutrients generally manifest their toxicity within a few weeks of dietary exposure by interfering with protein digestion protease inhibitors or by damaging cells lining the gastrointestinal tract lectins Delaney et al. Therefore, it is preferable to employ dosages that provide at least a tofold margin of safety Juberg et al. Additional toxicological studies may be indicated if the day study finds evidence of toxicity.

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They do not normally require acute tests on introduced proteins. Food safety scientists in regulatory agencies have not considered it necessary to conduct chronic testing of proteins introduced to date into GM crops based on the aforementioned considerations. These proteins are not considered to be toxic based on their known biochemical function. Residual levels of introduced proteins are present at very low levels in food products and are capable of being digested so that the potential for systemic absorption of the intact protein would likely be negligible.

Chronic testing is not generally needed to identify the potential toxicity of known protein toxins as this is usually manifest after acute or short term dietary exposure based on the known biochemical functions of protein toxins. Proteins can be denatured and inactivated during normal food processing, which may have an impact on dietary exposure.

Where there are low levels of dietary exposure to functionally intact introduced proteins, the TTC concept could be used to assess thresholds of exposure that have been shown to have very large margins of safety Delaney et al. Additional factors which will be discussed include 1 the relevance of HOSU to the safety assessment of proteins, 2 the effects of thermal or other kinds food processing conditions on dietary exposure to introduced proteins, 3 the potential for interactions between introduced proteins in combined-trait crops, and 4 the testing of proteins for genotoxicity.

According to this definition, referring to a specific protein that lacks direct evidence of being safely consumed i.


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EFSA has recommended that all introduced proteins without a HOSU be tested for safety in day repeat-dose toxicology testing unless there is reliable information to demonstrate their safety EFSA, a. To date, the completed day mouse studies on proteins introduced into GM crops have shown no evidence of adverse effects Delaney et al. The proteins evaluated in these day studies had also been assessed by the widely accepted weight-of-evidence approach e.

Therefore, the day study may not contribute any new, useful information where the weight of evidence indicates that there are no meaningful concerns raised during the risk assessment process. Thus the use of these studies should not be a routine requirement. Very few traditional whole foods, including those which contain anti-nutrients and toxins, have been subjected to systematic toxicological assessment. However, because such foods have a long HOSU, the protein components in such foods are generally regarded as safe to eat Constable et al. Some foods require special preparation to minimize the potential for associated health risks from consumption of natural protein anti-nutrients, such as trypsin inhibitors and lectins in soy or kidney bean.

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While the application of the HOSU concept may be somewhat subjective, it remains a useful tool for the hazard assessment of introduced proteins Delaney et al. There is general agreement that an introduced protein has a HOSU if it is identical to a protein that is already present in food and known to be safe for consumption at the levels expected in the GM crop. When the sequence of an introduced protein differs from the sequence of an endogenous protein already present in food, then the degree of acceptable similarity for safety assessment purposes needs to be decided on a case-by-case basis.

General protein biochemical principles can provide useful guidance. As previously noted, there can be considerable variation in amino acid content within families of proteins without changes in protein structure or function.


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As an example, 5-enolpyruvylshikimatephosphate synthase EPSPS is a key enzyme in the shikimate pathway, which is required for aromatic amino acid biosynthesis in plants, and is inhibited by the herbicide glyphosate. Moreover, structural comparison of the EPSPS proteins from canola, maize, rice, soy, Agrobacterium , and Escherichia coli Figure 1 indicates that sequence variation has little effect on overall protein structure and function. The position of glyphosate from the E. As described later, homologous proteins i. Introduction of a gene into a GM crop for the expression of a protein that is homologous to proteins with a HOSU can ensure a more robust safety assessment Delaney et al.

Homologous EPSPS proteins are ubiquitous in plant, yeast, and microbial food sources and show considerable variety in amino acid sequence, but share the same function in aromatic amino acid synthesis.