How Subchronic and Chronic Health Effects can be Neglected for GMOs, Pesticides

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Int J Biol Sci 2009; 5:438-443 ©Ivyspring International Publisher

_How Subchronic and Chronic Health Effects can be Neglected for GMOs,

Pesticides or Chemicals_ (http://www.biolsci.org/v05p0438.htm)

_http://www.biolsci.org/v05p0438.htm_ (http://www.biolsci.org/v05p0438.htm)

 

Review

How Subchronic and Chronic Health Effects can be Neglected for GMOs,

Pesticides or Chemicals

Gilles-Eric Séralini1,2 _✉_ (http://www.biolsci.org/v05p0438.htm#caddress)

, Joël Spiroux de Vendômois2, Dominique Cellier2,3, Charles Sultan2,4,

Marcello Buiatti2,5, Lou Gallagher6, Michael Antoniou7, Krishna R. Dronamraju8

1. University of Caen, Institute of Biology, Biochemistry, Esplanade de la

Paix 14032 Caen Cedex France.

2. CRIIGEN, 40 rue Monceau, 75008 Paris France

3. University of Rouen, LITIS EA 4108, 76821 Mont Saint-Aignan, France

4. University of Montpellier, School of Medicine, IGH, CNRS, France

5. University of Firenze, Italy

6. Institute for Environmental Science and Research, Ltd, Crown Research

Institute, Porirua, New Zealand

7. King's College London School of Medicine, Dept. Medical and Molecular

Genetics, London, United Kingdom

8. Foundation for Genetic Research, Houston, USA

How to cite this article:

Séralini GE, de Vendômois JS, Cellier D, Sultan C, Buiatti M, Gallagher L,

Antoniou M, Dronamraju KR. How Subchronic and Chronic Health Effects can

be Neglected for GMOs, Pesticides or Chemicals. Int J Biol Sci 2009;

5:438-443. Available from _http://www.biolsci.org/v05p0438.htm_

(http://www.biolsci.org/v05p0438.htm)

Abstract

Chronic health effects are increasing in the world such as cancers,

hormonal, reproductive, nervous, or immune diseases, even in young people.

During

regulatory toxicological subchronic tests to prevent these on mammalian

health, prior commercialization of chemicals, including pesticides and drugs,

or GMOs, some statistically significant findings may be revealed. This

discussion is about the need to investigate the relevant criteria to consider

those as biologically significant. The sex differences and the non linear

dose or time related effects should be considered in contrast to the claims

of a Monsanto-supported expert panel about a GMO, the MON 863 Bt maize, but

also for pesticides or drugs, in particular to reveal hormone-dependent

diseases and first signs of toxicities.

Keywords: Pesticides, GMO, MON 863, side effects, toxicological tests.

Introduction

Some contaminations or pollutions by pesticides [_1_

(http://www.biolsci.org/v05p0438.htm#B1) ] and other chemical residues [_2_

(http://www.biolsci.org/v05p0438.htm#B2) -_4_

(http://www.biolsci.org/v05p0438.htm#B4) ] affect

human and animal health, together with biodiversity. Thus it is important to

study potential mid and long-term toxicological effects during regulatory

tests prior to commercialization of chemicals, and not to test only

short-term or subchronic effects. This question has also been raised for GMOs

[_5_

(http://www.biolsci.org/v05p0438.htm#B5) ], especially those containing

pesticides, either because they tolerate (such as Roundup Ready soya) or

produce (such as Bt maize) these molecules (99 % of commercially cultivated

GMOs). This subject has been reviewed recently by Dronamraju [_6_

(http://www.biolsci.org/v05p0438.htm#B6) ].

Objectives

_Top_ (http://www.biolsci.org/v05p0438.htm#headingAtop)

_Introduction_ (http://www.biolsci.org/v05p0438.htm#headingA1)

_Objectives_ (http://www.biolsci.org/v05p0438.htm#headingA2)

_The protocol used to test GMOs..._

(http://www.biolsci.org/v05p0438.htm#headingA3)

_Sex-related and non-linear signs..._

(http://www.biolsci.org/v05p0438.htm#headingA4)

_Conclusion_ (http://www.biolsci.org/v05p0438.htm#headingA5)

_Acknowledgements_ (http://www.biolsci.org/v05p0438.htm#headingA6)

_References_ (http://www.biolsci.org/v05p0438.htm#headingA8)

Here we shall discuss more particularly the existing data on possible toxic

effects of a GMO on mammals, with putative relevance to humans, and with

the aim of commenting on current procedures and experimental protocols in

mammalian feeding experiments (Fig. _1_

(http://www.biolsci.org/v05p0438.htm#F1) ). Doull et al. [_7_

(http://www.biolsci.org/v05p0438.htm#B7) ]

indicated their general criteria needed to classify as biologically relevant

the

observed significant effects during 90d toxicological tests on mammals. The

example taken was for a GMO, a Bt maize called MON 863, producing in its

cells a new kind of modified insecticide Cry3Bb1, known as a toxin for

coleopterans. But these authors claim to apply the same criteria to other

products

such as pesticides and drugs. The history of the debate on the biosafety

of this GMO is paradigmatic, and it raises a series of general questions on

risk assessment of commercial transgenic crops and of pesticides or

chemicals. These considerations are crucial, since public health is concerned

and

their discussion may critically influence the decision to release in

particular some agricultural GMOs or not, and also to another extent the

economic

feasibility of this kind of project.

Figure 1

Comparison of regulatory toxicity tests generally performed in vivo on

mammals, for instance with rats, the most used model, before commercialization

of various products. These are GMOs used for food or feed, pesticides,

drugs, or the best tested chemicals. The choice of how to apply standards is

made by scientific commissions of regulatory instances. This figure does not

include reproductive, developmental or trans-generational tests that are

not requested for commercialized GMOs for food or feed. Nutritional tests are

not represented either because they do not require blood analyses, which

are very informative on health secondary effects. Some mammalian nutritional

tests are performed with pigs or cows, for instance for GMOs, and may last

longer with fewer animals. Subchronic toxicity tests are in the last case

performed, if any, only with rats for most GMOs. Then it is only with 10

animals fully assessed on 20 for each of two doses, and per sex. There are 3

mammalian species used for other products. This is to measure short-term

effects. The so-called chronic tests (lasting more than 3 months) give more

chances to reveal metabolic, nervous, immune, hormonal or cancer diseases.

They are widely performed for pesticides and drugs and for some chemicals

over a certain production, but not for actual commercialized GMOs released in

the environment (1995-2009). This is a matter of debate, since 99.9% of

those are genetically modified to contain new pesticide residues that they

tolerate (ex. Roundup Ready soya) or that they produce (ex. insecticides Bt in

maize, that are newly modified proteic toxins). (d: day; m: month; y:

year). (http://www.biolsci.org/v05/p0438/ijbsv05p0438g01.jpg) (Click on the

image to enlarge.)

The protocol used to test GMOs in regulatory in vivo tests with mammals

_Top_ (http://www.biolsci.org/v05p0438.htm#headingAtop)

_Introduction_ (http://www.biolsci.org/v05p0438.htm#headingA1)

_Objectives_ (http://www.biolsci.org/v05p0438.htm#headingA2)

_The protocol used to test GMOs..._

(http://www.biolsci.org/v05p0438.htm#headingA3)

_Sex-related and non-linear signs..._

(http://www.biolsci.org/v05p0438.htm#headingA4)

_Conclusion_ (http://www.biolsci.org/v05p0438.htm#headingA5)

_Acknowledgements_ (http://www.biolsci.org/v05p0438.htm#headingA6)

_References_ (http://www.biolsci.org/v05p0438.htm#headingA8)

Recently, Doull et al. [_7_ (http://www.biolsci.org/v05p0438.htm#B7) ]

offered a new contradictory analysis of Séralini et al. [_5_

(http://www.biolsci.org/v05p0438.htm#B5) ]. It was about the interpretation of

the only crude

data available from the longest toxicity test (90 days) on a mammal that

had been fed with MON 863. The original feeding experiment was performed by

Covance and Monsanto [_8_ (http://www.biolsci.org/v05p0438.htm#B8) ], with a

great experience of this kind of tests always designed in a similar

manner. They measured the effect of feed containing only two doses (11 and 33%

GM

in the equilibrated diet) and for only two periods of exposure (5 and 14

weeks). The goal is a debate on standards to be set to interpret admitted

significant effects [_7_ (http://www.biolsci.org/v05p0438.htm#B7) ] between

treated groups versus controls as biologically relevant or not in

toxicological tests in general.

There are several preliminary unsolved questions at stake to be answered

such as whether to prolong tests before commercial release, for instance up

to two years for GMOs, as is done for some pesticides or drugs, in order to

assess chronic effects not visible in short periods. There are also

questions regarding the appropriate number of concentrations of the putative

toxic

agent to be tested etc., and critical experimental criteria such as number

of animals to be used per dose or concentration to increase their

resolution power to obtain homogeneous and reliable significance levels in

outcome

measurement data.

However, the crude data on MON 863 were obtained by Monsanto for only one

mammalian species (instead of the three used for evaluations of pesticides

or drugs) and first classified as confidential by the Company which obtained

it (2002). The data was then used to obtain commercial release agreements

all over the world. After heated discussions in Europe concerning the

possible physiological effects provoked by this GMO, a decision in the German

Appeal Court allowed public access to the crude data (2005). Monsanto then

published its own interpretation of the data [_8_

(http://www.biolsci.org/v05p0438.htm#B8) ] in which it was concluded that the

MON 863 was safe to eat.

After careful analysis of the crude data, Séralini et al. [_5_

(http://www.biolsci.org/v05p0438.htm#B5) ] applied appropriate statistical

methodology

to test the effects of the Bt maize on mammalian health. First, GM fed rats

were compared to their closest isogenic controls, and then to the six

reference groups who were fed various other maize-based diets that Monsanto

added in the study. Data were compiled by organ, dose and timing of dietary

exposure. In addition, the effects on the rat metabolism of the diet

composition without GM maize was studied, comparing only control and reference

groups between them to avoid systematically linking these effects to the GM

diet. In the first instance Monsanto did not do such a statistical study ([_8_

(http://www.biolsci.org/v05p0438.htm#B8) ] and in commercial request file)

but only took into account effects between the GM fed rats at the highest

dose and all other groups. It is important to note that in order to isolate

the effect of the GM transformation process from other variables it is only

valid to compare the GMO (in this case MON 863) with its isogenic non-GM

equivalent. Therefore, the inclusion in the analysis of unrelated feeding

groups serves to confuse rather than clarify the effect of the MON 863 event.

The goal of the statistical analysis is to decide whether the consumption

of GMOs can be considered to have no effect (null hypothesis H0 true) or to

have an effect (H0 false) on the health of the rats. This analysis cannot

be reduced in the computation of a collection of p-values. Statistical

rejection of the null hypothesis H0 does not imply that the effect is

biologically significant. In the same way, failure to reject H0 does not mean

that

it is true. Therefore, the power of the hypothesis test must be assessed.

The power of a statistical test depends on the sample size (and therefore the

experimental design), the significance level of the test and the effect

size (which can be considered as biologically significant). This most

important issue is totally overlooked in the experimental design and the

statistical report made by Monsanto on MON 863. Moreover, any hypothesis which

is

not statistically significant with their reductive method is always excluded.

This disturbing oversight runs false negative results and a risk of health

consequences for millions of people and animals.

Sex-related and non-linear signs of toxicity

_Top_ (http://www.biolsci.org/v05p0438.htm#headingAtop)

_Introduction_ (http://www.biolsci.org/v05p0438.htm#headingA1)

_Objectives_ (http://www.biolsci.org/v05p0438.htm#headingA2)

_The protocol used to test GMOs..._

(http://www.biolsci.org/v05p0438.htm#headingA3)

_Sex-related and non-linear signs..._

(http://www.biolsci.org/v05p0438.htm#headingA4)

_Conclusion_ (http://www.biolsci.org/v05p0438.htm#headingA5)

_Acknowledgements_ (http://www.biolsci.org/v05p0438.htm#headingA6)

_References_ (http://www.biolsci.org/v05p0438.htm#headingA8)

In the MON 863 study, Séralini et al. [_5_

(http://www.biolsci.org/v05p0438.htm#B5) ] were also concerned by false

positive results, but concluded

that there were enough signs of toxicity to prolong the feeding experiments.

This is mostly because significant effects were concentrated in livers and

kidneys as main detoxification organs reacting in cases of food / chemical

contamination; there were at these levels some worrying physiological

profiles. Moreover, the effects of the MON 863 insecticide toxin itself are not

experimentally documented on mammalian cells. Furthermore, it remains a

possibility that there would be side effects due to insertional mutagenesis

during the GM transformation. For instance, the Séralini et al. [_5_

(http://www.biolsci.org/v05p0438.htm#B5) ] analysis showed evidence of a

significant

increase in blood glucose of 10% in GM-fed females, in triglycerides of

24-40%, overweight livers and enhanced liver/brain ratios (7%), small but

significant body weight gain (3.7%), and disturbed kidney parameters. When

comparing females eating GMOs to their closest controls eating the isogenic

line, there were signs of a possible pre-diabetic profile. In both sexes and

periods the profiles were different but it concerned liver and kidney

parameters.

From that, Doull et al. [_6_ (http://www.biolsci.org/v05p0438.htm#B6) ]

concluded that any effects with no clear dose-response relationship (which

should increase with dose) or with time are unrelated to the GM diet. We

consider that first of all, to a scientific point of view, choosing a priori 2

doses and 2 periods does not allow the assessment of a linear dose- or

period-related effect [_9_ (http://www.biolsci.org/v05p0438.htm#B9) -_11_

(http://www.biolsci.org/v05p0438.htm#B11) ]. Our hypothesis was to question the

possibility of subchronic or chronic health effects that were not or only

partially revealed by short-term tests. Several hormonal disrupting effects do

not linearly increase with time or dose, but present non-linear peaks in

the shape of U or J curves [_12_ (http://www.biolsci.org/v05p0438.htm#B12)

-_14_ (http://www.biolsci.org/v05p0438.htm#B14) ] at some periods or some

ranges of doses, depending on the age and exposure period of the test animals

[_15_ (http://www.biolsci.org/v05p0438.htm#B15) -_17_

(http://www.biolsci.org/v05p0438.htm#B17) ]. Secondly, a clear

histopathological study should be

published and studied in parallel to the biochemical effects found by

Monsanto or the Monsanto-supported expert panel [_7_

(http://www.biolsci.org/v05p0438.htm#B7) ]. It is possible that metabolic

changes precede, within 90

days, histopathological lesions that could appear afterwards. This is another

reason to prolong the experiments and may also solve the problem of

reproducibility. Simultaneously, the occurrence of similar effects in both

sexes

is an important criterion of toxicity for Doull et al. [_7_

(http://www.biolsci.org/v05p0438.htm#B7) ], which is not for us. Sex-dependent

differences

in chronic diseases resulting from chemical intoxication are well

established [_18_ (http://www.biolsci.org/v05p0438.htm#B18) , _19_

(http://www.biolsci.org/v05p0438.htm#B19) ]. The liver is itself a

sex-differentiated organ;

for example chemical sensitivity is different in males and females [_20_

(http://www.biolsci.org/v05p0438.htm#B20) ]. In Monsanto's data for these 3

month rat tests with Bt maize MON 863, for all rats including the six times

bigger group of normal control and reference animals eating non GM diets,

there were confirmed sex-differentiated effects in liver and kidneys

parameters (Fig._2_ (http://www.biolsci.org/v05p0438.htm#F2) A and B). Doull et

al. [_7_ (http://www.biolsci.org/v05p0438.htm#B7) ] also considered a normal

range of variations in undefined historical data, or compiled the closest

isogenic control with other reference groups that have diets different in

salt or sugars. This is not scientifically precise.

Figure 2

A. Principal Component Analysis for liver parameters in all rats of the

MON 863 experiment. It was performed according to Hotelling [_29_

(http://www.biolsci.org/v05p0438.htm#B29) ] in order to study the scattering of

the

different factors. 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. B. 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. (http://www.biolsci.org/v05/p0438/ijbsv05p0438g02.jpg)

(http://www.biolsci.org/v05/p0438/ijbsv05p0438g03.jpg) (Click on the image

to enlarge.)

Conclusion

_Top_ (http://www.biolsci.org/v05p0438.htm#headingAtop)

_Introduction_ (http://www.biolsci.org/v05p0438.htm#headingA1)

_Objectives_ (http://www.biolsci.org/v05p0438.htm#headingA2)

_The protocol used to test GMOs..._

(http://www.biolsci.org/v05p0438.htm#headingA3)

_Sex-related and non-linear signs..._

(http://www.biolsci.org/v05p0438.htm#headingA4)

_Conclusion_ (http://www.biolsci.org/v05p0438.htm#headingA5)

_Acknowledgements_ (http://www.biolsci.org/v05p0438.htm#headingA6)

_References_ (http://www.biolsci.org/v05p0438.htm#headingA8)

We assume that Séralini et al. [_5_

(http://www.biolsci.org/v05p0438.htm#B5) ] methodology can discriminate

potential false positive and GM-linked

effects, avoiding to some extent false negative ones, in the best way we can

do for this discussed and too limited protocol already in use for

commercialized GMOs. These GM-linked effects are then considered as signs of

toxicity

in the 90 days, not proofs of toxicity. The biological plausibility of a

subchronic or chronic side effect of the GM diet, linked to the new toxin in

the mammalian regimen, or due to the mutagenesis effect of the genetic

modification itself, is thus non negligible. Finally it should be stressed

that statistically significant effects of GM diets, or of residues of

pesticides that are contained by GMOs, have also been observed in other

instances

[_21_ (http://www.biolsci.org/v05p0438.htm#B21) -_25_

(http://www.biolsci.org/v05p0438.htm#B25) ], but not in all studies [_26_

(http://www.biolsci.org/v05p0438.htm#B26) , _27_

(http://www.biolsci.org/v05p0438.htm#B27) ]

enlightening the necessity of a case-by-case approach, and that the real

toxicological studies are quite limited up to date for that [_28_

(http://www.biolsci.org/v05p0438.htm#B28) ]. All these observations taken

together in our

opinions do not allow a clear statement of toxic effects, but to suggest them

as such, because they are clearly undeniable. Now, to any good researcher

similar results would mean that there is much to be improved in the planning

of experimental design; and thus to increase their resolution power to

obtain unequivocal statements, for instance increasing the duration and/or the

number of rats tested. Generally speaking it seems to us unbelievable that

a risk assessment carried out only on forty rats of each sex receiving GM

rich diets for 90 days (yielding results often at the limits of

significance) have not been repeated and prolonged independently. We should

overall

take into account the fact that the analysed GM product could be fed long-term

to people and animals of various ages and sexes, and with various

pathologies.

We call for more serious standardized tests such as those used for pestic

ides or drugs, on at least three mammalian species tested for at least three

months employing larger sample sizes, and up to one and two years before

commercialization, for GM food or feed specifically modified to contain

pesticide residues. We also call for a serious scientific debate about the

criteria for testing significant adverse health effects for pesticides or

chemicals, but overall for GM food or feed products, such as MON 863.

Acknowledgements

We thank François Roullier for Fig. _2_

(http://www.biolsci.org/v05p0438.htm#F2) and statistical studies.

Conflict of Interest

The authors have declared that no conflict of interest exists.

References

_Top_ (http://www.biolsci.org/v05p0438.htm#headingAtop)

_Introduction_ (http://www.biolsci.org/v05p0438.htm#headingA1)

_Objectives_ (http://www.biolsci.org/v05p0438.htm#headingA2)

_The protocol used to test GMOs..._

(http://www.biolsci.org/v05p0438.htm#headingA3)

_Sex-related and non-linear signs..._

(http://www.biolsci.org/v05p0438.htm#headingA4)

_Conclusion_ (http://www.biolsci.org/v05p0438.htm#headingA5)

_Acknowledgements_ (http://www.biolsci.org/v05p0438.htm#headingA6)

_References_ (http://www.biolsci.org/v05p0438.htm#headingA8)

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Author contact

✉ Correspondence to: Prof. Gilles-Eric Séralini, PhD, Institute of Biology

and CRIIGEN, University of Caen, Esplanade de la Paix, 14032 Caen Cedex,

France. Tel +33 2 31 56 56 84; Fax +33 2 56 53 20; Email: criigenunicaen.fr.

 

 

 

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