Int J Biol Sci 2009; 5:706-726 ©Ivyspring International Publisher

Research Paper

A Comparison of the Effects of Three GM Corn Varieties on Mammalian Health

Joël Spiroux de Vendômois¹, François Roullier¹, Dominique Cellier^1,2, Gilles-Eric Séralini^{1,3 ✉}

1. CRIIGEN, 40 rue Monceau, 75008 Paris, France
2. University of Rouen LITIS EA 4108, 76821 Mont-Saint-Aignan, France
3. University of Caen, Institute of Biology, Risk Pole CNRS, EA 2608, 14032 Caen, France

Abstract

We present for the first time a comparative analysis of blood and organ system data from trials with rats fed three main commercialized genetically modified (GM) maize (NK 603, MON 810, MON 863), which are present in food and feed in the world. NK 603 has been modified to be tolerant to the broad spectrum herbicide Roundup and thus contains residues of this formulation. MON 810 and MON 863 are engineered to synthesize two different Bt toxins used as insecticides. Approximately 60 different biochemical parameters were classified per organ and measured in serum and urine after 5 and 14 weeks of feeding. GM maize-fed rats were compared first to their respective isogenic or parental non-GM equivalent control groups. This was followed by comparison to six reference groups, which had consumed various other non-GM maize varieties. We applied nonparametric methods, including multiple pairwise comparisons with a False Discovery Rate approach. Principal Component Analysis allowed the investigation of scattering of different factors (sex, weeks of feeding, diet, dose and group). Our analysis clearly reveals for the 3 GMOs new side effects linked with GM maize consumption, which were sex- and often dose-dependent. Effects were mostly associated with the kidney and liver, the dietary detoxifying organs, although different between the 3 GMOs. Other effects were also noticed in the heart, adrenal glands, spleen and haematopoietic system. We conclude that these data highlight signs of hepatorenal toxicity, possibly due to the new pesticides specific to each GM corn. In addition, unintended direct or indirect metabolic consequences of the genetic modification cannot be excluded.

Keywords: GMO, toxicity, GM corn, rat, NK 603, MON 810, MON 863

1. Introduction

There is a world-wide debate concerning the safety and regulatory approval process of genetically modified (GM) crops and foods [1, 2]. In order to scientifically address this issue, it is necessary to have access to toxicological tests, preferably on mammals, performed over the longest time-scales involving detailed blood and organ system analyses. Furthermore, these tests should, if possible, be in accordance with OECD guidelines. Unfortunately, this has been a challenge since usually these are regulatory tests performed confidentially by industry prior to commercialization of their GM crops, pesticides, drugs or chemicals. As a result, it is more instructive to investigate the available data that allows comparisons of several GMOs consumptions on health effects. This will allow the most appropriate statistical analyses to be performed in order to avoid possible false positive as well as false negative results. The physiological criteria used to either accept or reject any GM significant effect as relevant should be made clear. Here we discuss sex-related, temporal, linear and non-linear dose effects which are often involved in the establishment of chronic and endocrine diseases.

We investigated three different GM corn namely NK 603, MON 810 and MON 863, which were fed to rats for 90 days. The raw data have been obtained by European governments and made publically available for scrutiny and counter-evaluation. These studies constitute a model to investigate possible subchronic toxicological effects of these GM cereals in mammals and humans. These are the longest in vivo tests performed with mammals consuming these GMOs. The animals were monitored for numerous blood and organ parameters. One corn (NK 603) has been genetically engineered to tolerate the broad spectrum herbicide Roundup and thus contains residues of this formulation. The two other types of GM maize studied produce two different new insecticides namely modified versions of Cry1Ab (MON 810) and Cry3Bb1 (MON 863) Bacillus thuringiensis-derived proteins. Therefore, all these three GM maize contain novel pesticide residues that will be present in food and feed. As a result, the potential effects on physiological parameters, due either to the recognized mutagenic effects of the GM transformation process or to the presence of the above mentioned novel pesticides within these plants can be evaluated in animal feeding studies.

2. Materials and Methods

2.1. Experimental design

The three animal feeding studies were conducted in two different laboratories and at two different dates; at Monsanto (Missouri, USA) for NK 603 and MON 810 (June 7, 2000) and at Covance Laboratories Inc. (Virginia, USA) for MON 863 (March 14, 2001) on behalf of Monsanto. The young adult male and female rats, approximately 4-6 week-old, were of the Sprague-Dawley albino strain Crl:CD(SD)IGS BR^®, (obtained from Charles River Laboratories Inc., NY, USA). The animals (400 per GMO; 200 for each sex) were randomized for similar body weight distribution. In fact, there were only two treated groups for each sex (20 animals each consuming specific GM maize feed). Only 10 rats were measured per group for blood and urine parameters and served as the basis for the major statistical analyses conducted. In addition, the investigators claimed that OECD guidelines and standards were followed. For each type of GM maize, only two feeding doses were tested per sex. This consisted of either 11 or 33% GM maize in an otherwise equivalent equilibrated diet; that is when the diet contained only 11% GM maize, the difference was made up by adding 22% non-GM maize (varieties not indicated). There were also two comparative control groups fed diets containing similar quantities of the closest isogenic or parental maize variety. Furthermore, groups of animals were also fed with diets containing one of six other normal (non-GM) reference maize lines; the same lines for the NK 603 and MON 810 tests, but different types for the MON 863 trials. We note that these unrelated, different non-GM maize types were not shown to be substantially equivalent to the GMOs. The quantity of some sugars, ions, salts, and pesticide residues, do in fact differ from line to line, for example in the non-GM reference groups. This not only introduced unnecessary sources of variability but also increased considerably the number of rats fed a normal non-GM diet (320) compared to the GM-fed groups (80) per transformation event, which considerably unbalances the experimental design. A group consisting of the same number of animals fed a mixture of these test diets would have been a better and more appropriate control. In addition, no data is shown to demonstrate that the diets fed to the control and reference groups were indeed free of GM feed.

2.2. Data collection

The raw biochemical data, necessary to allow a statistical re-evaluation, should be made publically available according to European Union Directive CE/2001/18 but unfortunately this is not always the case in practice. On this occasion, the data we required for this analysis were obtained either through court actions (lost by Monsanto) to obtain the MON 863 feeding study material (June 2005), or by courtesy of governments or Greenpeace lawyers. We thank the Swedish Board of Agriculture, May 30, 2006 for making public the NK 603 data upon request from Greenpeace Denmark and lawyers from Greenpeace Germany, November 8, 2006 for MON 810 material. This allowed us to conduct for the first time a precise and direct side-by-side comparison of these data from the three feeding trials with these GMOs.

Approximately 80 different biochemical and weight parameters, including crude and relative measures (Table A, Annexes), were evaluated in serum and urine after 5 and 14 weeks of feeding. We classified these per organ (markers by site of synthesis or regulation). These organs weighed at the end of the experimental period, along with the whole body were: adrenal glands, brain, gonads, heart, kidneys, liver, and spleen. In addition, some parameters measured were related to bone marrow (blood cells) and pancreas (glucose) function. Unfortunately, some important measurements serving as markers for liver function were not conducted for technical or unknown reasons. This included gamma glutamyl transferase after 90 days feeding, cholesterol and triglyceride levels in the NK 603 and MON 810 trials, and cytochrome P450 family members in all cases. In addition, important sex difference markers were also ignored such as blood sex or pituitary hormone levels. Furthermore, it is well known and present in OECD guidelines that measurements should be conducted for at least 3 different experimental points to study dose- or time-related effects. Contrastingly and for reasons that are not stated, in all three studies for all three GMOs, only 2 doses and periods of feeding were measured, which makes it difficult to evaluate dose and cumulative effects. We have in a first instance indicated lacking values for different parameters (Annexes, Tables B, C, D).

2.3. Statistical power related to the experimental design

The most fundamental point to bear in mind from the outset is that a sample size of 10 for biochemical parameters measured two times in 90 days is largely insufficient to ensure an acceptable degree of power to the statistical analysis performed and presented by Monsanto. For example, concerning the statistical power in a t test at 5%, with the comparison of 2 samples of 10 rats, there is 44% chance to miss a significant effect of 1 standard deviation (SD; power 56%). In this case to have a power of 80% would necessitate a sample size of 17 rats. Therefore, the statistical power is insufficient in these studies to allow an a priori dismissal of all significant effects. Indeed, this is true overall with the amplitude of the effects that can usually be observed within three months, in the case of usual chronic toxicity appearing after one year of treatment. Hence, the lack of rejection of the null hypothesis at 5% does not mean that this hypothesis is true. Thus, the assessment of statistical power is absolutely necessary to understand the undetectable size effect; the statistical power depends on the sample and effect size, and the level of the test. This is exemplified when Monsanto performed one-way analysis of variance (ANOVA) calculations at 5% with a sample size of 10 animals for 10 groups. In this case the probability of not detecting a medium size effect [3] (0.5 SD for a t test for instance) is about 70% (power of the test 30%). However, the fact is that within 90 days, a chronic toxicity has a maximum chance of giving rise to a medium rather than large size effects. The disturbance of parameters at the beginning of a disease is generally less important than at its end or as time progresses. Therefore, the protocol has to be drastically improved at this level, and as a result we consider that based on the analysis as presented by Monsanto that it fails to demonstrate that the consumption of these GM maize feeds was indeed safe as claimed. Any sign of toxicity should be taken into consideration to justify the prolongation of the experiment, or, if this is not possible, to reassess the statistical analysis, and to propose a scientifically valid physiological interpretation of any findings relating to disturbed functional parameters on a per organ basis. This was the ultimate objective of this investigation.

In reality, in their report containing the raw data and statistical analysis, Monsanto did not apply in any case their chosen and described statistical methods. Only parametric tests (one-way ANOVA under homoscedasticity hypothesis and Student t tests on contrasts) were employed. Moreover, to select significant results, they only contrasted the data sets from the 33% GM maize feeding groups (for NK 603 and MON 810) with all reference groups. Moreover, their biological interpretation of statistically significant results differs from case to case. In particular, sex differences were frequently used to reject pathological significance, despite the fact that this was without measuring effects on sex hormone levels. They also used the lack of linear dose-related effects, which is almost inevitable given that only two feeding doses were measured, to declare the diet as safe, as proposed for MON 863 GM maize [4]. In the MON 863 experiments, the authors still failed to apply their declared methodology, which was slightly different. The ANOVA and contrast analysis (33% GM feeding dose versus controls) were in this case the determining criteria for evaluation of statistical significance, but only if the mean of the 33% GM feeding group was outside the range of the mean of the reference cohorts. All this increases noticeably the risks of false negative results.

Consequently, based on the clear inadequacy of the statistical power used to refute toxic effects (for instance the unquestionable large size effects in this study), knowing also that billions of people and animals can consume these products prior to the performance of appropriate in vivo safety evaluation, we applied an appropriate, experimentally validated statistical analytical methodology [5], elements of which are described below.

2.4. Statistical methods employed

We first repeated the same statistical analysis as conducted by Monsanto to verify descriptive statistics (sample size, means, and standard deviation) and ANOVA per sex, per variable and for each of the three GMO. For all that, the normality of the residues was tested using the Shapiro test and the homoscedasticity (homogeneity of the variances) using the Bartlett test. In the case where the Shapiro and Bartlett tests were non significant (*p > 0.05 and **p > 0.01, respectively) we performed an ANOVA [6, 7], and in the case of heteroscedasticity the approximate Welch method was used. In the case where the Shapiro test was significant, we performed the Kruskal-Wallis rank sum test [7, 8].

We then analyzed the effects of the GM maize varieties on each sex and each diet by pairwise comparisons of the parameters of GM-fed rats versus control groups, and subsequently to the unrelated non-GM maize reference groups. The statistical differences between reference and control groups were calculated in order to study the effects of the different normal diets per se (due to differences in salts, sugars, minerals, vitamins, pesticides, etc composition), and indicated by contrast to Monsanto’s work (see legend Table 1). In order to select the appropriate two-tailed comparison test [7], we again studied first normality (Shapiro test) and variance equality (F test). According to the results, we performed the adapted test; that is, an unpaired t test, a Welch corrected t test or a Mann-Whitney test (which is generally more appropriate with a sample size of 10). To perform multiple pairwise comparisons, we used the False Discovery Rate approach (FDR, [9]) to calculate adjusted p-values, in order to limit the rate of false positives to 5%. We preferred Benjamini and Yekutieli’s method [10] rather than that of Benjamini and Hochberg [11] as the parameters under investigation are not independent. In addition, after centering and scaling the data, Principal Components Analysis (PCA, [12]) was performed in order to study the scattering of the different factors (sex, period, diet, dose and group). Finally, we established per group for each rat and by parameter the representations and paired tests corresponding to the temporal changes between the two feeding periods.

We used the R language [7] version 2.5 for all statistical computations [13] with the appropriate package: pwr package for power studies, the bioconductor’s multtest package for FDR [14-15] and the ADE4 package [16, 17] for multivariate analysis.

3. Results

We have previously reported indications of toxicity in rats fed with MON 863 GM maize for 90 days [5]. However, these signs of toxicity alone do not constitute proof of adverse health effects. We have therefore extended our initial analysis on the MON 863 feeding data by collectively compiling the significant differences observed in the physiological and biochemical parameters measured in feeding trials of rats with each of the three GM maize varieties MON 863, MON 810 and NK 603 (Tables 1, 2; Annex Table E). When we then initially compare all p-values in our calculations with those of Monsanto (significant and non significant differences, Annex Table E), we obtain ratios of 432/452 (NK 603), 435/450 (MON 810) and 442/470 (MON 863). By employing our statistical methods even if we reached a concordance with Monsanto’s results (Annex Table E), the level of precision of the main effects and their interpretation are highly different. Therefore, we then progressed to consider only relative differences over 5% (Tables 1 and 2).

3.1. NK 603

We first evaluated the results for the NK 603 feeding trials. The observations shown in Table 1 with relative differences versus controls reveal that of 23 significantly different effects that are supposed to be due to this GM maize, 18 are in males (raw means with SEM; Annex Table F). The repartition of effects is thus sex-dependent. In addition, in general liver (Fig. 1) and kidney (Fig. 2) parameters in all rats are sex differentially expressed. This is evident not only in the experiments involving NK 603, independently of the treatment at week 14, but also at week 5 (data not shown), but similarly observed in the MON 810 and MON 863 feeding tests (Annex Fig. A- Fig. D).

Males are clearly more sensitive than female animals to show physiological disturbances when fed NK 603. This is not observed for all three GM maize varieties. Moreover, most effects appear to be dose-dependent since 83% of male effects emerge only at the 33% feeding level (15/18), the highest GM maize concentration in the diet (Table 1). The maximal mean differences are observed in male kidney parameters.

Urine phosphorus, for instance, is importantly disturbed in a dose-dependent manner and at both 5 and 14 week periods of feeding and hence reproducible over time. The significant effect at this level does not appear to be a false positive result (week 5, 33%, adjusted p<0.003 for FDR calculated according to Benjamini and Yekutieli), considering that all parameters were not independent. Comparable results were also obtained for relative lymphocyte and neutrophil differences (all for males, week 14, 33%, adjusted p<0.005).

 Table 1 

Differences between NK 603-fed rats and controls. Study of the GMO effects, which are indicated by mean differences (%) for each parameter with the corresponding control group per sex and per dose. The significant differences versus controls (*p < 0.05, **p < 0.01), for all the parameters measured in the subchronic feeding tests, are presented. The parameters were grouped by organs according to the sites of synthesis or classical indicators of dysfunction. They were indicated for all groups only if they showed at least for one sex or one diet a significant and relatively ± 5% difference to the mean. The animals were male (m) or female (f) young adult rats fed during 5 or 14 weeks with the GM maize NK 603 (11 or 33% in the diet) and compared with controls fed with a ''substantially equivalent'' isogenic maize line. The parameters were measured for 10 rats, except for the organ weights (20 rats), obtained only at the end of the experiment. In single-boxed numbers, we indicate the statistical differences between GMO-fed rats and controls, which are not found between the mean of the six reference groups and controls. A difference between reference and control groups could indicate an effect of the diet per se. In double-boxed numbers, among the effects due to the GMO, are indicated the statistical differences between the GMO groups and the mean of the six reference groups (which have not even eaten a genetically linked variety of maize as the control and the GMO treated groups). (p): Differences for the indicated parameters are not significant by a nonparametric test but by a parametric one; all other differences by both. “Lar Uni Cell” means percent of large unnucleated cell count.

(Click on the image to enlarge.)

 Fig 1 

Principal Component Analysis for liver parameters of all rats in the NK 603 feeding trial. The scheme obtained for parameters at week 14 explains 66.65% of the total data variability (inertia) expressed on 2 axes (49.84% for factor 1; 16.81% for factor 2), scale d=2. This demonstrates the clear separation of parameters values according to sex.

(Click on the image to enlarge.)

 Fig 2 

Principal Component Analysis for kidney parameters of all rats in the NK 603 experiment. The scheme obtained for parameters at week 14 explains 44.78% of the total data variability (inertia) expressed on 2 axes (27.27% for factor 1; 17.51% for factor 2), scale d=2. This demonstrates the clear separation of parameters values according to sex.

(Click on the image to enlarge.)

Among 18 GM maize-related effects versus controls, 11 show that groups of reference and control animals are similar in these cases (Table 1, framed values). However 6 GM-linked effects are also significant versus all reference groups (Table 1, double framed values). At week 5, these relative maximal effects concern a diminution of blood and increase of urine creatinine clearance, and then a diminution of blood urea nitrogen. This is not observed at week 14 (Fig. 3a,b). Even so, the kidney parameters measured are clearly the most reactive in both sexes; 52% of significant effects are noticed at this level, but kidney parameters represent only 31% of those measured in total. We also observe that ion concentrations are enhanced in urine of male GM fed rats. Besides this, crude and relative liver weights are also affected at the end of the maximal (33%) GM maize feeding level as well as that of the heart which for corresponding parameters to a comparable extent, showed up to an 11% weight increase. Variations in females are far less frequent (5/23), with no clear significant differences except for urine phosphorus (major relative difference versus controls) and blood potassium (versus all groups).

3.2. MON 810

Feeding of MON 810 resulted in 11/15 significant effects in females (Table 2, crude means with SEM; Annex Table G), which again highlights sex-differential effects. The sex-dependency for the measured parameters in liver and kidney is observed for all rats (Annex Fig. A & Fig. B). The significant GM-maize linked effects are generally detected either after 14 weeks of consumption or at a high GM feed dose in the diet. Parameters affected relate to: blood cells, adrenal gland and kidney weights, an increase in blood urea nitrogen and higher spleen weight. Significantly disturbed parameters in males are concentrated in liver function at the 33% GM-maize feeding level in the diet, with a slight diminution in general serum albumin production. All disturbances are <20% and p-values are significant but >1% (Table 2, starred values). However, p-values adjusted for FDR are not significant.

 Table 2 

Differences between MON 810-fed rats and controls. For details, see legend Table 1.

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3.3. MON 863

We have already described our evaluation of the MON 863 rat feeding studies [5]. Sex-dependency is well marked in this case also for the spreading of all parameters in liver and kidney (Annex Fig. C & Fig. D). The 34 significant GM-linked effects are equally distributed among males (16) and females (18). This contrasts with what is observed with NK 603 and MON 810. Nevertheless, 9/16 (56%) of males show statistically significant differences in kidney compared to 4/18 females. However, although kidney parameters represent only 37.5% of all measurements, these data show a male-specific effect in kidney function. This trend is somewhat opposite to what is seen in liver parameters where males showed significant effects in 5/16 cases whereas the rate is 9/18 in females. Male rats also appear more sensitive to kidney disturbances at the higher GM feeding dose (11 effects at 33% versus 5 at 11%).

Additional statistically significant differences include (i) a serum glucose and triglyceride increase (up to 40%) in females versus controls, together with a higher liver (7%) and overall body (3.7%) weight, (ii) elevated creatinine, blood urea nitrogen and urine chloride excretion in females, but greater variation in male kidney function (creatinine, and in urine sodium, potassium and phosphorus), (iii) up to a significant kidney weight decrease (7%) with a noticeable chronic nephropathy in males [18], (iv) a decrease (3.3%) in male body weights and (v) some liver function differences in males (albumin, globulin, as in females, plus alanine aminotransferase), although none of the FDR-adjusted p-values are significant.

Furthermore, we have also measured in this study for the first time the differences between time-related variations (at weeks 5 and 14) for this GM maize variety, at each feeding dose versus controls. We have represented these variations for each rat for all parameters. Among these, the significant variations corresponding to disturbed parameters are illustrated (Figs. 4-7). Our analysis clearly shows that female rat triglyceride levels vary between 5 and 14 weeks of feeding (Fig. 4; p=0.025). Triglyceride levels increase over time within the GM maize feeding group and whilst decreasing in the case of controls. Again in females, the increase in creatinine caused by MON 863 is more evident with longer feeding periods at an 11% level (Fig. 5; p=0.022). Another significant difference (p=0.011), which we observe is a reciprocal variation in female urine chloride excretion (Fig. 6). In the males, only urine potassium decreases over time with the consumption of GM feed but increases in controls (Fig. 7, p=0.011).

In summary, the tendency for physiological disturbance is characteristic of almost all rats of all GM-fed treatment groups, and physio-pathological profiles differ according to dose or sex.

 Fig 3 

Kinetic plot for urine creatinine clearance in male rats fed NK 603. For each rat at 33% GM maize feed level (a) and controls (b) the lines represent the variations between week 5 and 14 for this parameter (ml/min/100 g body weight). The dotted thick line represents the means variation.

(Click on the image to enlarge.)

 Fig 4 

Kinetic plot for female rat triglyceride levels in the MON 863 feeding trial. For each rat at 11% GM maize feed level (a) and controls (b) the lines represent the variations between week 5 and 14 for this parameter (mg/dL). The dotted thick line represents the mean variation.

(Click on the image to enlarge.)

 Fig 5 

Kinetic plot for creatinine levels in female rats fed MON 863. For each rat at 11% GM maize feeding level (a) and controls (b) the lines represent the variations between week 5 and 14 for this parameter (mg/dL). The dotted thick line represents the mean variation.

(Click on the image to enlarge.)

 Fig 6 

Kinetic plot for urine chloride excretion in female rats fed MON 863. For each rat at 33% GM feed level (a) and controls (b) the lines represent the variations between week 5 and 14 for this parameter (meq/time). The dotted thick line represents the mean variation.

(Click on the image to enlarge.)

 Fig 7 

Kinetic plot for urine potassium in male rats fed MON 863. For each rat at 11% GM maize level (a) and controls (b) the lines represent the variations between week 5 and 14 for this parameter (mmol/L). The dotted thick line represents the mean variation.

(Click on the image to enlarge.)

4. Discussion

If a “sign of toxicity” may only provoke a reaction, pathology or a poisoning, a so-called “toxic effect” is without doubt deleterious on a short or a long term. Clearly, the statistically significant effects observed here for all three GM maize varieties investigated are signs of toxicity rather than proofs of toxicity, and this is essentially for three reasons. Firstly, the feeding trials in each case have been conducted only once, and with only one mammalian species. The experiments clearly need to be repeated preferably with more than one species of animal. Secondly, the length of feeding was at most only three months, and thus only relatively acute and medium-term effects can be observed if any similar to what can be derived in a process such as carcinogenesis [19, 20] or after endocrine disruption in adults [21]. Proof of toxicity is hard to decide on the basis of these conditions. Longer-term (up to 2 years) feeding experiments are clearly justified and indeed necessary. This requirement is supported by the fact that cancer, nervous and immune system diseases, and even reproductive disorders for examples can become apparent only after one or two years of a given intervention treatment under investigation, but they will not be evident in all cases after three months of administration when first signs of toxicity may be observed [22, 23]. In addition, large effects (e.g. 40% increase in triglycerides) in all likelihood will be missed with the protocol of the current studies, since they are limited by the number of animals used in each feeding group and by the nature of the parameters studied. Thirdly, the statistical power of the tests conducted is low (30%) because the experimental design of Monsanto (see Materials and Methods). However, it is important to note that these short-term (3-month) rat feeding trials are the only tests conducted on the basis of which regulators determine whether these GM crop/food varieties are as safe to eat as conventional types. Given that these GM crops are potentially eaten by billions of people and animals world-wide, it is important to discuss whether the experimental design, the statistical analyses and interpretations originally undertaken are appropriate and sufficient.

Any differences observed in comparison with the isogenic variety, has to be taken into account as a potential physiological disruption. This is particularly valid since any statistically differences that are observed are highly unlikely to be arising from population variation as in the case of humans due to the genetic homogeneity of the rat strain used in these studies. Moreover, the standardized conditions of rat maintenance employed, which are stated to be in accordance with OECD standards [24, 25], make the diet the only factor of variation in the protocol. Thus, the GM maize component of the test diet is the major factor of difference if one directly compares treated rats and controls. This is indicated by stars in the Tables expressing the total characteristics of GM-linked physio-pathological profiles. The other results that are encompassed by frames in the Tables highlight that effects from the GM maize are over and above those observed for any of the six different diets; for instance, over that observed with a diet richer in salt or sugar over the 3-month feeding period. These additional “control” diets could have been avoided with an experimental design that truly focused on the general question of GM toxicity.

The first observation that we were able to make was that there is a good general concordance between our data and the results of Monsanto as presented in their original confidential reports, in particular on the proportion of statistically significant observations. However, the methodology we employed revealed different effects, which completely changed the interpretation of the experimental results. For instance, the sex differences are fully taken into account in our study, which contrasts with the first published comments of these data [18, 26, 27]. We evaluated and took note of differences in the reaction of male and female rats to the GM maize test diets based on accepted and now classical knowledge of endocrinology [28], embryology [29, 30], physiology [31, 32], enzymology or hepatology [33] demonstrating sex-specific physio-pathological effects. Indeed, our present results fully confirmed the sex-specific distribution of effects on kidney and liver parameters for all rats in all three studies analyzed here. An identical effect in both sexes would have been exceptional, like with strong or acute toxicity. This is obviously not the case here. In addition, we considered equally important effects that were neither time nor dose related, even if we detailed these when observed in the results. The proof for a linear dose dependency, as requested by Doull and coll. [4] to determine the significance of effects, is impossible with only two feeding points with no prior standardization. Furthermore, a metabolic reaction either physiological or pathological is not necessarily linear in its response [34, 35]. Again, this does not invalidate a description of effects appearing at the higher GM feed doses.

Even if the significant differences are around 5% of all comparisons for each GM corn, we believe that they either constitute a very good possibility to represent signs of toxicity, or at the very least should be considered as sufficiently strong evidence to justify a repeat of the experiments incorporating longer feeding times, for several reasons. Firstly, the arguments of Hammond and coll. [18, 26, 27] from Monsanto and Doull and co-workers [4] cannot demonstrate that the statistically significant GM-feed linked differences are not physiologically relevant [2]. Secondly, very few GM-feed effects appear only at the low dose or after the shortest (5 week) feeding period; 8.6% for NK 603, 6.6% for MON 810, 14.7% for MON 863 (Tables 1, 2, and ref. [5]). Thirdly, the marked sex difference effects observed for the GM maize feeding groups, in several instances, are found for physiological markers in all rats. Therefore, there is little probability that these effects were a random, chance occurrence. Fourthly, our stringent statistical tools allowed differentiation of GM-feed impacts from differences arising from variation in the composition of other reference diet. This is the first time that such an analysis has been conducted. Fifthly, there is a lack of cancer, hormonal or hepatic functional marker measurements (for example, oncogene expression, sex steroid hormone levels, cytochrome P450 levels), that could have provided explanatory insight into the results. The lack of availability of this type of data may be of benefit to those that doubt the current observations provide evidence of potential signs of toxicity. Sixthly, the physiological and biochemical parameters found to be disrupted in these feeding studies frequently provide a coherent, GM-specific picture of events, which corresponds and is in support of the generally admitted concept held by industry and regulators that GM crops and food should be considered on a case by case basis. Seventhly, several double-framed outcomes encompass all dietary effects only after the 3 month period of feeding. Last but not least, the most marked and most numerous effects are on organs involved in detoxification like the kidney and liver, usually reached after a diet-linked toxicity.

For instance in the NK 603 study statistically significant strong urine ionic disturbances and kidney markers imply renal leakage. This includes creatinine (increased urinary clearance), together with its diminution in the blood, and the decrease in urea nitrogen. Blood creatinine reduction has in some cases been found to be associated with muscle problems. It is therefore perhaps of note that the heart, as a very representative muscle organ was affected in the GM feeding groups. The possibility of renal porosity as evidenced by these data may be due to the presence of residues of Roundup herbicide, that are present in GM crop varieties such as the NK 603 maize investigated here. We have previously demonstrated that glyphosate-based herbicides such as Roundup are highly toxic at very low concentrations to human embryonic kidney cells [36], inducing a decrease in viability, noticeably via inhibition of mitochondrial succinate dehydrogenase.

The deficiency in kidney function we highlight to be present in male rats is different between animals fed NK 603 and MON 863. The latter is characterized by an increase in plasma creatinine levels and retention of ions, which were associated with a chronic interstitial nephropathy, as originally admitted in the Monsanto MON 863 report and by Hammond and coll. [18]. However, this disturbance in kidney function was dismissed in their conclusions because the strain of rat used in the feeding studies is apparently sensitive to this type of pathology, especially during aging, which was not the case here. However, this reasoning was admitted by various regulatory authorities (EFSA, CGB in France). These arguments again appear flawed as the rats were still relatively young, 5 months by the end of the experimental period and therefore below the age when they might be expected to spontaneously develop kidney diseases. More importantly, these kidney effects are clearly MON 863-specific since they are not observed with all three GM maize varieties and the control groups, and therefore could not have arisen from an inherent genetic predisposition of the strain of rat used, which in addition was the same in all cases. Overall, no kidney parameters in male animals are disrupted in the MON 810 feeding group, even though sensitivity to toxics appears in general to be greater in this sex [37, 38]. An additional contributory factor to this disturbance in kidney function could arise from either novel unintended toxic effect caused by the inherent mutagenic effect of the GM technology, or possibly due to the new mutant forms of Bt toxin produced by MON 863, which is completely different from that engineered into MON 810. However, MON 810-fed females have a slight kidney weight enhancement, which may correspond with a mild hyperplasia usually seen in association with immune inflammatory processes. A re-evaluation of the histological slides from these animals would be of interest to test this hypothesis. Furthermore, analysis of some pertinent markers of kidney function such as arterial tension or angiotensin levels are lacking from these studies. This type of investigation including controls where animals are fed a normal diet spiked with the corresponding purified Bt toxin, would allow a more rational and precise interpretation of the results.

In the case of the MON 863 feeding trials, which have previously been discussed [5] and are at the center of a debate [2, 4], new results have been obtained by the re-evaluation of the data with more powerful statistical methods as we present here. In female rats, there is a risk of becoming pre-occupied with the reactions already ascribed to the GM feeding group since several parameters indicate increases in circulating glucose and triglyceride levels, with liver function parameters disrupted together with a slight increase in total body weight [5]. This physiological state is indicative of a pre-diabetic profile. We demonstrate here that in female animals triglycerides profile, creatinine or urine chloride excretion are differentially and specifically altered over time in comparison to control groups, depending on the GMO dose. All these disruptions and differences taken together could be interpreted as clear signs of toxicity.

The effects found after only 5 weeks of feeding or at lower 11% feed dose, cannot be neglected simply on the basis that they are less frequently observed. Compensation or recuperation could occur after tissues are harmed, as possibly observed in the case of mice fed a diet containing Roundup Ready GM soy [39]. Peak inflammatory processes may occur in damaged tissues, followed by a regeneration phase as observed after bacteria/viral infection or a chemical toxic insult [40, 41]. For instance, urine potassium decreases in male rats over time in the GM MON 863 group at the 11% feed dose, which was not observed in all but one of the controls. This effect is specifically time-dependent and thus does not appear to be artefactual. This type of punctual regeneration may be part of a carcinogenic process, and clearly even if total recovery occurs, this should not be taken as a sign that the GM feed is safe.

5. Conclusions

Patho-physiological profiles are unique for each GM crop/food, underlining the necessity for a case-by-case evaluation of their safety, as is largely admitted and agreed by regulators. It is not possible to make comments concerning any general, similar subchronic toxic effect for all GM foods. However, in the three GM maize varieties that formed the basis of this investigation, new side effects linked to the consumption of these cereals were revealed, which were sex- and often dose-dependent. Effects were mostly concentrated in kidney and liver function, the two major diet detoxification organs, but in detail differed with each GM type. In addition, some effects on heart, adrenal, spleen and blood cells were also frequently noted. As there normally exists sex differences in liver and kidney metabolism, the highly statistically significant disturbances in the function of these organs, seen between male and female rats, cannot be dismissed as biologically insignificant as has been proposed by others [4]. We therefore conclude that our data strongly suggests that these GM maize varieties induce a state of hepatorenal toxicity. This can be due to the new pesticides (herbicide or insecticide) present specifically in each type of GM maize, although unintended metabolic effects due to the mutagenic properties of the GM transformation process cannot be excluded [42]. All three GM maize varieties contain a distinctly different pesticide residue associated with their particular GM event (glyphosate and AMPA in NK 603, modified Cry1Ab in MON 810, modified Cry3Bb1 in MON 863). These substances have never before been an integral part of the human or animal diet and therefore their health consequences for those who consume them, especially over long time periods are currently unknown. Furthermore, any side effect linked to the GM event will be unique in each case as the site of transgene insertion and the spectrum of genome wide mutations will differ between the three modified maize types. In conclusion, our data presented here strongly recommend that additional long-term (up to 2 years) animal feeding studies be performed in at least three species, preferably also multi-generational, to provide true scientifically valid data on the acute and chronic toxic effects of GM crops, feed and foods. Our analysis highlights that the kidneys and liver as particularly important on which to focus such research as there was a clear negative impact on the function of these organs in rats consuming GM maize varieties for just 90 days.

Abbreviations

GM: genetically modified; m: modified toxin by mutagenesis.

Acknowledgements

We thank Michael Antoniou for assistance and comments on the compilation of this manuscript. The support of the French Ministry of Research is gratefully acknowledged.

Greenpeace contributed to the start of the investigations by funding first statistical analyses in 2006, the results were then processed further and evaluated independently by the authors.

Conflict of Interests

The authors declare that there is no conflict of interest.

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Author contact

✉ Correspondence to: Prof. Gilles-Eric Séralini, Institute of Biology, EA 2608, University of Caen, Esplanade de la Paix, 14032 Caen Cedex, France. Phone +33 2 31 56 56 84; Fax +33 2 56 53 20; Email: criigenunicaen.fr.

Authors Biographies

Prof. Gilles-Eric Séralini is a molecular biologist at the University of Caen, team leader and author of books on environment and GMOs. He was expert for the French government (1998-2007) and the European Union at the WTO level and for the council of Ministers on GMOs (2003, 2008), president of the scientific council for independent research on genetic engineering (CRIIGEN), and receiver of Order of Merit for his scientific career (2008). Correspondence: criigen@unicaen.fr

Dr. Joël Spiroux de Vendômois is doctor in medicine, specialist in environmental pathologies and co-organizer of the first European meeting on environmental pathologies.

François ROULLIER is a statistician.

Dr. Dominique CELLIER is a researcher in bioinformatics, co-organizer of a Master 2 in bioinformatics and statistics at the University of Rouen.

ANNEXES

 Fig A 

Principal Component Analysis for liver parameters in all rats of the MON 810 experiment. The scheme obtained for parameters at week 14 explains 62.48% of the total data variability (inertia) expressed on 2 axes (47.46% for factor 1; 15.02% for factor 2), scale d=2. This demonstrates the clear separation of parameters values according to sex.

(Click on the image to enlarge.)

 Fig B 

Principal Component Analysis for kidney parameters in all rats of the MON 810 experiment. The scheme obtained for parameters at week 14 explains 43.16% of the total data variability (inertia) expressed on 2 axes (24.87% for factor 1; 18.29% for factor 2), scale d=2. This demonstrates the clear separation of parameters values according to sex.

(Click on the image to enlarge.)

 Fig C 

Principal Component Analysis for liver parameters in all rats of the MON 863 experiment. The scheme obtained for parameters at week 14 explains 42.42% of the total data variability (inertia) expressed on 2 axes (32.01% for factor 1; 10.41% for factor 2), scale d=2. This demonstrates the clear separation of parameters values according to sex.

(Click on the image to enlarge.)

 Fig D 

Principal Component Analysis for kidney parameters in all rats of the MON 863 experiment. The scheme obtained for parameters at week 14 explains 47.73% of the total data variability (inertia) expressed on 2 axes (26.95% for factor 1; 20.78% for factor 2), scale d=5. This demonstrates the clear separation of parameters values according to sex.

(Click on the image to enlarge.)

Received 2009-7-23
Accepted 2009-11-17
Published 2009-12-10

프랑스 정부의 생명공학 자문기구인 HCB는 유럽에서 GM작물 중 유일하게 상업적으로 재배되고 있는 몬산토사의 유전자 조작 옥수수 MON 810의 환경에 대한 영향을 평가하기 위해서는 보다 더 많은 연구가 필요하다고 밝혔습니다.

지난 목요일 출간된 자문위원회의 의견은 프랑스 정부의 요청으로 제출된 것이며, 프랑스 정부는 지난해 환경에 대한 우려가 제기됨에 따라 MON 810 유전자 조작 옥수수의 재배를 금지했습니다.

유럽식품기준청(EFSA)은 지난 6월 유전자조작 옥수수 MON 810이 일반적인 옥수수와 마찬가지로 인체와 동물에 안전하다는 입장을 발표했습니다. 다시 말해 유전자조작 옥수수 MON 810이 인체와 환경에 위험이 되지 않는다는 입장을 밝혔습니다.

 EFSA의 GMO 패널은 해충 저항 능력이 있는 DNA를 주입한 유전자 조작 옥수수 MON 810이 안전상 우려를 불러일으키지 않으며, 유전자 조작의 안정성에 대한 충분한 증거가 확보됐다는 결론을 내렸습니다.

그러나 프랑스 정부를 비롯한 유럽연합 국가들은 유럽식품기준청(EFSA)의 이러한 유전자조작 옥수수  MON 810 옹호가 불충분하다며 비판을 제기했습니다.

지난 5월 EU 국가들은 EU 집행위의 요청을 무시하고 오스트리아와 헝가리에 유전자조작(GM) 옥수수 경작을 허용하는 방안을 거부했습니다. 또한 프랑스, 그리스, 룩셈부르크 정부 등도 GM 옥수수 경작을 금지하고 있습니다.

그런데 이번에 HCB가 유전자 조작 옥수수 MON 810의 잠재적 결함을 평가하기 위해 추가적인 연구를 할 필요가 있다는 의견을 밝힘에 따라 프랑스 등 EU 국가의 정부와 EU 집행위 및 유럽식품기준청(EFSA) 등의 유전자조작 옥수수에 대한 서로 상반된 입장의 대립이 더욱 첨예하게 노출될 것으로 예상됩니다. 프랑스 등 EU 국가의 정부의 입장에서는 유전자조작 옥수수 MON 810 재배금지 조치에 대한 정당성을 어느정도 확보한 셈이라고 볼 수 있습니다.

 HCB는 표적으로 삼지 않은 해충(곤충)대한 피해 또는 표적으로 삼은 해충(곤충)운데 작물에 대한 저항성의 발달 등을 추가로 연구할 필요가 있다는 밝혔으며, 표적으로 삼지 않은 무척추동물의 개체수의 증가 또는 감소에 중대한 변화가 있는지를 모니터링 하기 위해서는 몇 년의 시간이 소요된다고 얘기했습니다.

위원회는 또한 다른 재배 기술과 견주어 MON 810 유전자조작 옥수수의 유용성이 확립되기 위해서는 추가적인 작업이 필요하며, 특히  저항성을 가지도록 설계된 MON 810 이 표적으로 삼지 않는 곤충에 중요한 영향을 끼치지 않는다는 점을 확립하는 것이 중요하다고 밝혔습니다.

HCB 위원회의 보고서는 유전자조작 작물의 안전성에 관한 이슈가 프랑스 내에서 얼마나 분란을 일으키는 이슈인가를 여실히 보여주고 있습니다. 농장연합, 환경단체, 과학단체, 의회기구 등으로 이루어진 소위원회 투표에서 MON 810은 14대 11로 이익(14)보다 손해(11)가 많은 것으로 나타났습니다.

반면 전혀 다른 의견이 발표되기도 했습니다. 프랑스정부의 식품안전 기구인 프랑스 식품위생안전청(AFSSA)은 유럽식품기준청(EFSA)처럼 MON 810은 추가적인 연구가 필요하다는 의견에도 불구하고 인간이나 동물의 건강에 안전하다는 입장을 되풀이하고 있습니다.

 MON 810의 안전성 논란에 대한 로이터 통신사의 뉴스 원문은 다음과 같습니다.

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French body says Monsanto maize needs more study

Tuesday, December 22 06:38 pm

More research is needed into Monsanto’s genetically modified maize MON 810, the only biotech crop commercially grown in Europe, to assess its environmental impact, a French advisory body said. Skip related content

The opinion given by biotech committee HCB, published on Tuesday, was requested by the French government, which last year banned cultivation of MON 810 citing environmental concerns.

In an debate about whether to renew the license for the maize type, France and other European Union states have criticized as insufficient a favorable opinion in June from the European Food Safety Authority (EFSA).

HCB called for further studies to evaluate potential drawbacks in MON 810, such as damage to non-targeted insects or the development of resistance to the crop among targeted pests.

“The only way to highlight … a significant increase or decrease in populations of non-targeted invertebrates is to implement monitoring over several years,” the HCB said.

The committee also said more work was needed to establish the benefits of the maize type versus other growing techniques, especially in areas not significantly affected by the pests MON 810 was designed to resist.

The views of the committee would be presented by France in European discussions on MON 810, which are due to lead to a conclusion by EU technical representatives in February, an official at the French environment ministry said.

But HCB’s paper also showed how divisive the issue is within France. A vote by a subcommittee made up of farm unions, environmental associations, scientific and parliamentary bodies, on the overall value of MON 810 showed a narrow majority of 14 to 11 saying the maize had more disadvantages than benefits.

In a separate opinion also released on Tuesday, French food safety body AFSSA reiterated that, like EFSA, it considered MON 810 to be as safe as conventional maize for human and animal health, although it also called for further research.

(Reporting by Gus Trompiz, editing by Anthony Barker)

밀은 전세계적으로 옥수수, 쌀 다음으로 생산량이 많은 곡식입니다. 2007년 전 세계 밀 생산량은 6억7백만 톤이었습니다. 밀은 빵, 비스킷, 케잌, 아침식사용 시리얼, 파스타, 국수, 꾸스꾸스를 만들어 먹기도 하고, 밀을 발효시켜서 맥주, 보드카, 곡주 등을 만들어 먹기도 합니다.

지금까지 유전자조작 밀은 시판된 적이 없는데… 제3세계 국가들은 안전성의 문제 때문에 서양(북미 및 유럽) 사람들이 자신들의 주식인 밀은 유전자조작을 하지 않는다면서 ‘음모론’을 제기하고 있기도 합니다.

지난 2004년 세계 제1의 유전자조작 기업 몬산토사는 유전자조작 밀의 개발을 추진하다가 북미대륙의 곡물상들과 밀재배 농민들의 반대와 미국산 밀을 수입하는 수입국에서 일반 밀이 유전자조작 밀에 오염될 우려가 있다는 이유로 모든 미국산 밀을 수입하지 않을 것이라는 반대에 부딛혀 유전자조작 밀 개발의 잠정적 중단을 선언했습니다.

그런데 세계시장에서 미국의 밀 수출량이 차지하는 비율이 1973~74년 50%에서 최근 20%로 하락하는 지경에 이르자 드디어 미국의 밀 생산업자들과 몬산토사의 이해관계가 맞아떨어져 유전자조작 밀을 재배하고 시판하려는 움직임을 보이고 있는 것 같습니다. 

다음은 12월 19일자 영국의 가디언지에 실린 “유전자조작 밀이 몰려온다(유전자조작 밀이 다가온다)”는 내용의 기사 전문입니다.

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GM wheat is on its way

Five years after scrapping its trials, Monsanto calculates that the time is now ripe for GM wheat to make a comeback

Henry Miller and Colin Carter

출처 : guardian.co.uk, Saturday 19 December 2009 16.00 GMT
http://www.guardian.co.uk/commentisfree/cifamerica/2009/dec/19/gm-wheat-monsanto

Wheat is a critical staple crop, supplying much of the world’s dietary protein. In 2007 world production was 607m tonnes, making it the third most-produced cereal after maize and rice. The grain is used to make breads, biscuits, cakes, breakfast cereal, pasta, noodles, and couscous, and for fermentation to make beer, vodka, and grain alcohol. Up to now, wheat has not benefited from the application of modern genetic engineering that has revolutionised the farming of maize, cotton, canola and soy. But that is about to change.

By 2004, Monsanto, the world’s leader in the production of seeds for genetically-engineered crops, had made substantial progress in the development of genetically-engineered wheat varieties for North America. But suddenly in that year, the company scrapped its wheat programme, in part because of opposition from North American grain merchants and growers, as well as concerns that some major foreign importers would reject imports of all American wheat because they could be “contaminated” with genetically engineered varieties. European countries and Japan, which have traditionally imported about 45% of US wheat exports, have been resistant to genetically engineered crops and food derived from them.

In addition, food manufacturers doubted that the introduction of genetically engineered wheat would lead to a significant improvement in their profits because the cost of wheat is typically only a small fraction of inputs for most processed food products, and food processors were afraid of losing market share if environmental and consumer activists were to organise boycotts of food products containing “biotech” wheat. For the last 25 years, activists have opposed agricultural biotechnology, in spite of proven environmental, humanitarian and economic successes.

Monsanto’s abdication gave competitors outside the US the opportunity to become the first to adopt new technologies for genetically improved and lower cost wheat, relinquishing what could have been a first-mover advantage – the privileged position of the initial occupant of a market segment.

However, American growers and millers have had a change of mind. In 2006, a coalition of US wheat industry organisations called for access to genetically-engineered wheat varieties with enhanced traits, and a survey released in February 2009 by the US national association of wheat growers found that more than three-quarters of US farmers wanted access to genetically engineered varieties with resistance to pests, disease, drought and frost. Such varieties are important as plant scientists and farmers continue to battle diseases such as leaf rust, the world’s most common wheat disease, which can lead to yield loss of up to 20%. In Kansas, the heart of the US wheat belt, for example, leaf rust is the most significant pest, in 2007, it destroyed a shocking 14% of the wheat crop.

American growers, caught in the middle between the inclinations of some of their largest customers and the developers of new wheat varieties, lost out on substantial benefits when Monsanto opted not to follow through with creating genetically-engineered wheat. This left the field (literally and figuratively) to countries such as Australia and China, which are now ahead in their research and field trials of genetically-engineered wheat. For example, the German plant science and chemical company Bayer and Australia’s Commonwealth Scientific and Industrial Research Organisation (CSIRO) are collaborating to develop wheat varieties with higher yield, more efficient nutrient use and greater tolerance against drought.

These developments are important for several reasons. Wheat farming is a struggling industry in the US, in large part because it has not received the technological boost from recombinant DNA technology that has benefited the corn and soybean industries. US wheat acreage is down by about one-third from its peak in the early 1980s, due to reduced profitability compared with alternative crops – in spite of the price of a bag of wheat flour having soared from $10 to a peak of $36 during the past 36 months. As a result, the US’s position as a leading wheat exporter has declined over several decades, from a high of 50% of world exports in 1973-74 to only around 20% currently.

Five years after letting their biotech wheat research program wither, Monsanto recently revealed plans to resurrect it. The agribusiness company not only announced in July 2009 that it would resume development of genetically engineered wheat varieties, it also further demonstrated its commitment by buying WestBred, a Montana-based wheat-breeding company that specialises in wheat germplasm, the plant’s genetic material.

Greater productivity in wheat farming achieved with improved varieties would confer an important environmental dividend: wheat is the largest crop in the world in terms of area cultivated (220m hectares) and is the second largest irrigated crop (each bushel produced requires 11,000 gallons of water on average), so enhanced productivity would conserve both farmland and water. (A more direct approach is being taken by scientists at Egypt’s Agricultural Genetic Engineering Research Institute, who have performed at least five years of field trials of drought- and salt-tolerant wheat created by transferring genes from barley into a local wheat variety.)

Monsanto’s volte-face reflects the company’s assessment that the various relevant factors – technology, business, public policy and customer acceptance – had now become favourable, and was spurred by the world food crisis that saw a tripling of the price of wheat and certain other food crops during 2008. But it will likely take at least eight years until the first varieties of Monsanto’s genetically-engineered wheat could be commercialised in the United States.

Monsanto and the US wheat industry may already have been relegated to the position of second mover, and whoever wins the race to get desirable genetically engineered wheat varieties to the marketplace will enjoy a strong cost advantage and attract market share in many importing countries.

Henry Miller is a fellow at the Hoover Institution and the author of The Frankenfood Myth. Colin Carter is professor of agricultural and resource economics at the University of California at Davis

식량난의 ‘희망’인가 ‘GMO<유전자 변형 농산물> 장사꾼’ 인가

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