The use of whole food animal studies in the safety assessment of genetically modified crops: Limitations and recommendations

Figures & data

Table 1. Summary of global regulatory requirements for WF studies in support of approval to import/plant GM crops.

Country/region*	Regulatory requirement for WF toxicity studies†	Regulatory guidance (if publically available)‡
North America
Canada	Not routinely required.	Regulatory guidelines available at http://www.hc-sc.gc.ca/fn-an/gmf-agm/guidelines-lignesdirectrices/index-eng.php
United States	Not routinely required.	Regulatory guidelines are not published online, but the following link provides examples of regulatory decisions taken without requirement for a WF study: http://www.epa.gov/oppbppd1/biopesticides/pips/pip_list.htm
Mexico	Not routinely required.	Regulatory guidelines available at: http://www.hgm.salud.gob.mx/descargas/pdf/dirgral/marco_juridico/reglamentos/regla_22.pdf
Central and South America
Argentina	Not routinely required/case-by-case.	Regulation of GM crops in Argentina has been summarized by Burachik (2012).
Brazil	Not routinely required.	Regulatory guidelines for biotechnology products available at: http://www.ctnbio.gov.br/index.php/content/view/142.html
Asia/Pacific
Australia/New Zealand	Not routinely required; however, if a WF study is submitted to the EU it is also provided to Australia/New Zealand.	Regulatory guidelines available at: http://www.foodstandards.gov.au/code/changes/pages/applicationshandbook.aspx
China	Requirement to conduct WF studies in country.	Huang & Yang (2011)
India	Not routinely required.	Guidelines and protocols for the safety assessment of foods derived from available at: http://www.icmr.nic.in/guide/Guidelines%20for%20Genetically%20Engineered%20Plants.pdf; http://igmoris.nic.in/files%5CCoverpage1.pdf
Indonesia	Not routinely required.	The National Biosafety Framework of the Republic of Indonesia is available at http://www.unep.org/biosafety/files/IDNBFrep.pdf
Japan	Not routinely required.	Standards for the Safety Assessment of Genetically Modified Foods (Seed Plants) are available at: http://www.fsc.go.jp/english/standardsforriskassessment/gm_kijun_english.pdf
Philippines	Not routinely required.	http://docs.biotecsur.org/informes/en/inventario/4_normativa_ms.pdf http://www.unep.org/biosafety/files/KRNBFrep.pdf
South Korea	Not routinely required.	The National Biosafety Framework of the Republic of Korea, which includes an example of a safety evaluation of a GM food in Korea, is available at: http://www.unep.org/biosafety/files/KRNBFrep.pdf
Taiwan	Not routinely required.	Specific guidance/regulations not readily available and/or not available in English.
South Africa	Not routinely required.	Specific guidance/regulations not readily available and/or not available in English.
European Union/Europe	WF studies are required for all single trait GM crops; not routinely required for multiple trait (“stacked”) GM crops when single trait crops have already been tested.	For the EU, EFSA (2011) provides specific advice for performing WF studies, available at: http://www.efsa.europa.eu/de/efsajournal/pub/2438.htm The recommendation to perform WF studies is on a case-by-case basis according to OECD Test No. 408 (OECD, 1998) and on EFSA’s review of the role of animal trials in GM crop safety assessment (EFSA, 2008a).
Russia	Requirement to conduct WF studies in country.	Specific guidance/regulations not readily available and/or not available in English.

Codex, Codex Alimentarius Commission; EFSA, European Food Safety Authority; FAO, Food and Agriculture Organization of the United Nations; GM, genetically modified; IFBiC, International Food Biotechnology Committee; OECD, Organization for Economic Cooperation and Development; WF, whole food; WHO, World Health Organization.

*Selected countries growing 50 000 hectares or more of GM crops officially approved for planting in 2012 are included (James, 2012). The following countries also grew more than 50 000 hectares of GM crops but are not included because their regulatory documents are either not finalized or are evolving or are not readily accessible: Bolivia, Burkina Faso, Chile, Myanmar, Paraguay, and Uruguay. This does not mean that there is no regulatory process in place for GM crops in these countries. The inclusion of Russia is not based on the number of hectares planted but on knowledge of GM crop registration requirement in this country through the experience of IFBiC Task Force 10 members.

†Regulatory requirements for WF studies are based primarily on the experience of IFBiC Task Force 10 members with GM crop safety assessment in the countries included in Table 1 and secondarily on available regulations and guidelines. For the purpose of this table, regulatory experience is critical because regulations and guidances do not necessarily specify requirements for WF toxicity studies. In countries/regions where WF studies are not routinely required, a range of options may be pursued, including the option to request a WF or other toxicology study if such a study will address a data gap in the safety assessment.

‡Published regulatory documents are not publically available or readily accessed for all countries.

Table 2. Summary of peer-reviewed nutrition, performance and/or safety studies of genetically modified (GM) feeds conducted on livestock and poultry*.

Test species	Test crop	Study duration	Control	Reference group†	% in feed‡	References
Cattle (dairy cows)	HT soy (Gly)	28 d	Parental	1	10.2	Hammond et al. (1996b)
	Bt maize	21–28 d	Iso	0	75–80	Donkin et al. (2003)
	HT maize (Gly)	28 d	Iso	2	63	Grant et al. (2003)
	Bt maize	28 d	Iso	2	66.7	Grant et al. (2003)
	HT maize (Gly)	28 d	Iso	2	57.3	Ipharraguerre et al. (2003)
	Bt maize	35 d	Conventional	0	35	Yonemochi et al. (2003)
	HT maize (Gluf)	84 d	Iso	2	33.1	Phipps et al. (2005)
	Bt + HT maize (Gly)	28 d	Iso	0	45.1	Calsamiglia et al. (2007)
	HT alfalfa (Gly)	28 d	Conventional	2	39.7	Combs and Hartnell (2008)
	Bt cottonseed	28 d	Iso	0	40	Mohanta et al. (2010)
	Bt maize	25 mo	Iso	0	71	Steinke et al. (2010)
	Bt + HT maize (Gluf)	28 d	Iso	0	44	Brouk et al. (2011)
	Bt cottonseed	28 d	Iso	0	40	Singhal et al. (2011)
Cattle (steers)	HT maize (Gly)	92 d	Iso	2	75	Erickson et al. (2003)
	HT maize (Gly)	94 d	Iso	2	73	Erickson et al. (2003)
	HT maize (Gly)	144 d	Iso	2	79.5	Erickson et al. (2003)
Cattle (bulls)	Bt + HT maize	246 d	Parental	0	Ad lib.sileage	Aulrich et al. (2001)
Cattle (calves)	Bt maize	84 d	Iso	0	43.3	Shimada et al. (2006)
Swine	Bt + HT maize	14 d	Parental	0	50	Aulrich et al. (2001)
	HT maize	24 d	Parental	0	30	Böhme et al. (2001)
	HT sugar beet	24 d	Parental	0	30	Böhme et al. (2001)
	Bt + HT maize	98–114 d	Parental	0	70	Reuter et al. (2002a)
	Bt + HT maize	NI¶	Parental	0	70	Reuter et al. (2002b)
	HT soy (Gly)	4 mo¶	Iso	0	14–24.3‡	Cromwell et al. (2002)
	HT maize (Gly)	103 d	Iso	2	68.1–81.8	Hyun et al. (2004)
	HT maize (Gly)	NI¶	Iso	2	65–77	Hyun et al. (2004)
	HT rice (Gluf)	98 d	Iso	1	72–85.8	Cromwell et al. (2005)
	Bt maize	104 d	Iso	2	68.7–82.5	Hyun et al. (2005)
	Bt maize	NI¶	Iso	2	65–76	Hyun et al. (2005)
	Bt maize	NI¶	Combined§	0	78–83	Custodio et al. (2006)
	Bt maize	NI¶	Combined§	0	70–76.5	Custodio et al. (2006)
	HT wheat (Gly)	NI¶	Iso	4	70–85	Peterson et al. (2008)
	Bt + HT maize (Gluf)	4 mo¶	Iso	1	69.1–81.9	Stein et al. (2009)
	Bt maize	NI¶	Iso	0	70	Yonemochi et al. (2010)
	Bt maize	30 d	Iso	0	38.9	Walsh et al. (2012)
Poultry	HT soy (Gly)	42 d	Parental	0	26.6–32.9	Hammond et al. (1996b)
(broiler chickens)	Bt maize	38 d	Iso	0	61.4–67.4	Brake & Vlachos (1998)
	HT maize (Gly)	38–40 d	Parental	5	50–60	Sidhu et al. (2000)
	Bt + HT maize	30–35 d	Parental	0	50	Aulrich et al. (2001)
	Bt maize	49 d	Conventional	0	70	Yonemochi et al. (2002)
	Bt maize	42 d	Iso	1	48.2–63.6	Brake et al. (2003)
	Bt maize	42 d	Iso	5	57.1–62.7	Taylor et al. (2003)
	Bt + HT maize (Gly)	42 d	Iso	5	55.2–60.5	Taylor et al. (2003)
	Bt maize	35 d	Parental	0	73.6	Tony et al. (2003)
	HT canola (Gly)	42 d	Iso	6	25	Taylor et al. (2004)
	Bt maize	39 d	Iso	0	60	Aeschbacher et al. (2005)
	IP maize	49 d	Iso	2	55.0–66.0	Brake et al. (2005)
	Bt maize	42 d	Iso	0	48.7–62.7	Rossi et al. (2005)
	Bt + HT maize (Gly)	43–44 d	Iso	5	54.7–59.4	Taylor et al. (2005)
	HT soy (ALSi, Gly)	42 d	Iso	3	22.5–31	McNaughton et al. (2007)
	HT soy (Gly)	42 d	Iso	6	61.4–64.8	Taylor et al. (2007a)
	Bt maize	42 d	Iso	4	55.1–59.6	Taylor et al. (2007b)
	Bt + HT maize (Gly)	42 d	Iso	4	54.8–58.5	Taylor et al. (2007b)
	Bt + HT maize (Gly)	42 d	Iso	6	57.3–59.4	Taylor et al. (2007c)
	HT maize (ALSi, Gly)	42 d	Iso	3	58.5–71.5	McNaughton et al. (2008)
	HT maize	42 d	Iso	3	50–60	Herman et al. (2011a)
	HT soy	42 d	Iso	3	32–40	Herman et al. (2011b)
	HT maize + HT soy	42 d	Iso	3	91.5–94.2	McNaughton et al. (2011a)
Poultry (laying hens)	Bt + HT maize	10 d	Parental	0	50	Aulrich et al. (2001)
	Bt maize	6 months	Iso	0	60	Aeschbacher et al. (2005)
	Bt + HT maize (Gluf)	3 months	Iso	1	64.8	Jacobs et al. (2008)
	High oleic soy	3 months	Iso	2	23.5	Meija et al. (2010)
	HT maize + HT soy	3 months	Iso	3	84.6–86.3	McNaughton et al. (2011b)

ALSi, acetolactate synthase inhibitor (herbicide tolerant); Bt (Bacillus thuringiensis), crop expresses one or more Cry proteins; Gluf, glufosinate tolerance; Gly, glyphosate tolerance; GM, genetically modified; HT, herbicide tolerant (if Gluf, Gly, or ALSi is not specified, crop is tolerant to one or more alternative herbicides); Iso, near-isogenic line (has similar background genetics to test line but lacks the gene insert for the GM trait); IP, insect-protected (expresses non-Cry protein); NI, not indicated.

*Peer-reviewed, published livestock and poultry feeding studies on insect pest-protected and herbicide-tolerant crops are summarized. The list is not intended to be comprehensive, and small numbers of studies using sheep or quail are not included. A review by Flachowsky et al. (2007) includes some studies not summarized in this table.

†Non-GM reference groups used for establishing historical control normal range.

‡Percent incorporation (w/w) of all forms of the test crop(s) in feed (i.e. grain and/or silage); ranges represent changes in test crop levels in feed over the course of the study in grower/finisher pigs and starter/grower/finisher broiler chickens.

¶Duration approximate or not indicated for some swine studies in which animals were terminated when they reached a specific body weight.

§Control corn was a mixture of several non-transgenic inbred lines.

Table 3. Summary of experimental designs in peer-reviewed, published short-term (21-to-30-day) rodent toxicology studies conducted on whole foods derived from genetically modified crops*.

Crop	Sponsor	Dose group	Group size	Reference group†	Control	% in diet‡	References
Bt potato	Monsanto	NI	NI	0	Parental	NI	Lavrik et al. (1995)
HT soy, processed	Monsanto	1	10/sex	0	Iso	24.8	Hammond et al. (1996b)
HT soy, unprocessed	Monsanto	2	10/sex	0	Iso	5/10	Hammond et al. (1996b)
Bt cotton	China	2	6/sex	0	Parental	5/10	Chen et al. (1996)
Sweet pepper, virus resistant	China	3	10/sex	0	Rodent diet	NI	Chen et al. (2003)
Tomato, virus resistant	China	3	10/sex	0	Rodent diet	NI	Chen et al. (2003)
HT oilseed rape	Monsanto	2	10/sex	0	Parental	5/15	EFSA, 2004
HT oilseed rape	Monsanto	2	10/sex	8	Parental	10	EFSA, 2004
Bt potato	NI	1	12 males	1	Iso	30	El Sanhoty et al. (2004)
Potato, virus resistant	NI	1	8; sex NI	2	Iso	40	Juskiewicz et al. (2005)
Potato, non-browning	NI	1	NI	0	Iso	NI	Llorente et al. (2011)

Bt (Bacillus thuringiensis), crop expresses one or more Cry proteins; HT, herbicide tolerant; Iso, near-isogenic line (has similar background genetics to test line but lacks the gene insert for the GM trait); NI, not indicated.

*The duration of most studies was 28–30 days; the study duration was 21 days for Juskiewicz et al. (2005). Test GM foods were administered in feed. A selection of clinical observations, hematology, blood chemistry, organ weights, and gross and microscopic pathology were performed.

†Non-GM reference groups used for establishing historical control normal range.

‡Percent incorporation (w/w) of test crops in the rodent diet.

Table 4. Summary of experimental designs in peer-reviewed, published subchronic (90-day) rodent toxicology studies conducted on whole foods derived from genetically modified crops*.

Crop	Sponsor	Dose group	Group size	Reference group†	Control	% in diet‡	References
Bt tomato†	RIKILT	1	12/sex	0	Iso	10	Noteborn et al. (1995)
HT soy	Japan	1	5/sex	0	Iso	30	Teshima et al. (2000)
Bt maize	Japan	1	8/sex	0	Iso	5/50	Teshima et al. (2002)
Ht maize	Monsanto	2	20/sex	6	Iso	11/33	Hammond et al. (2004)
HT soy	China	3	10/sex	0	Iso	30/60/90	Zhu et al. (2004)
Bt/HT maize	Monsanto	2	20/sex	6	Iso	11/33	EFSA (2005a)
Bt/HT maize	Monsanto	2	20/sex	0	Iso	11/33	EFSA (2005b)
Bt/HT maize	Monsanto	2	20/sex	0	Iso	11/33	EFSA (2005c)
Bt maize	Monsanto	2	20/sex	0	Iso	11/33	EFSA (2005d)
HS potato (amylopectin)	BASF	3	5/sex	0	Iso	5	EFSA (2006a)
HT sugar beet	KWS SAAT AG/Monsanto	2	NI	4	Iso	2/5	EFSA (2006b)
Bt maize	Monsanto	2	20/sex	6	Iso	11/33	Hammond et al. (2006a)
Bt maize	Monsanto	2	20/sex	6	Iso	11/33	Hammond et al. (2006b)
Bt cotton	Dow	1	12/sex	3	Iso	10	Dryzga et al. (2007)
HT maize	Syngenta	2	12/sex	0	Iso	10/41.5	EFSA (2007)
Bt/HT maize	Pioneer	2	12/sex	3	Iso	11/33	MacKenzie et al. (2007)
Bt/HT maize	Pioneer	1	12/sex	2	Iso	35	Malley et al. (2007)
Bt rice	EU and Canada	1	16/sex	0	Iso	60	Schrøder et al. (2007)
Lectin rice (snowdrop)	EU, China, India	1	16/sex	0	Iso	60	Poulsen et al. (2007a)
Lectin rice (PHA-E)	EU and China	1	8/sex	0	Iso	60	Poulsen et al. (2007b)
HT soy	Pioneer	1	12/sex	3	Iso	20	Appenzeller et al. (2008)
High oleic soy	Pioneer	1	12/sex	3	Iso	20	Delaney et al. (2008a)
HT soy	Monsanto	2	20/sex	6	Iso	5/15	EFSA (2008b)
Bt maize	Monsanto	2	20/sex	0	Iso	11/33	EFSA (2008c)
Bt maize	Pioneer	2	10/sex	0	Iso	50/70	He et al. (2008)
Bt/HT maize	Monsanto	2	20/sex	6	Iso	11/33	Healy et al. (2008)
HT maize	Pioneer	1	12/sex	3	Iso	35–38	Appenzeller et al. (2009b)
Bt/HT maize	Pioneer	1	12/sex	3	Iso	34	Appenzeller et al. (2009a)
Bt maize	Syngenta	2	12/sex	0	Iso	10/41.5	EFSA (2009b)
Lysine maize	Pioneer	2	10/sex	0	Iso	30/76	He et al. (2009)
High amylose rice	China	1	10/sex	0	Iso	70	Zhou et al. (2011)
HT soy	BASF	2	10/sex	4	Iso	11/33	Chukwudebe et al. (2012)
IP maize	Syngenta	2	12/sex	0	Conventional	10/41.5	EFSA, 2012a
High oleic, HT soy	Monsanto	1	12/sex	3	Conventional, HT soy	30	EFSA, 2012b
Bt/HT maize	China	3	10/sex	1	Iso	12.5/25/50	Liu et al. (2012)
High oleic/HT soy	Pioneer	3	10/sex	0	Iso	7.5/15/30	Qi et al. (2012)
rhIGF-1 rice	China	2	16/sex	0	Iso	20	Tang et al. (2011)
HT maize	China	3	10/sex	0	Iso	12.5/25/50	Zhu et al. (2013)

Bt (Bacillus thuringiensis), crop expresses one or more Cry proteins; HS, high starch; HT, herbicide tolerant; IP, insect protected (non-Bt); Iso, near-isogenic line (has similar background genetics to test line but lacks the gene insert for the GM trait); NI, not indicated; PHA-E, phytohemagglutinin-E; rhIGF-1, recombinant human growth factor-1.

*Test GM foods were administered in feed. A selection of clinical observations, hematology, blood chemistry, organ weights, and gross and microscopic pathology were performed.

†Non-GM reference groups used for establishing historical control normal range.

‡Percent incorporation (w/w) of test crops in the rodent diet.

Table 5. Examples of limitations in experimental design, analyses, and interpretation in some WF toxicity studies with GM crops.

Best practices for WF toxicity studies	Deficiencies observed	References
Experimental design
Identity of test and control substances	The identity of the GM test substance was not confirmed through an appropriate analytical method. Confirmation of correct control and test crop presence in diet was not conducted.	Brake & Evenson (2004), Ermakova (2007), Ewen & Pusztai (1999), Kiliç & Akay (2008), Malatesta et al. (2002a, 2002b, 2003, 2005, 2008)
Use of appropriate control crops	The control crop was not of similar genetic background to the GM test crop. In some studies the control was simply identified as a “wild” variety.	Brake & Evenson (2004), Ermakova (2007), Ewen & Pusztai (1999), Malatesta et al. (2002a, 2002b, 2003, 2005, 2008), Rhee et al. (2005)
	The test and control substances were not produced under similar environmental conditions. and/or no information was provided on the production of test and control substances.	Ermakova (2007), Ewen & Pusztai, (1999), Malatesta et al. (2002a, 2002b, 2003, 2005, 2008), Rhee et al. (2005)
Acceptable levels of contaminants (eg pesticides, mycotoxins, other microbial toxins) in control and test crops	Study results were not interpreted in light of differences in antinutrient or mycotoxin levels in test and control diets.	Velimirov et al. (2008), Carman et al (2013)
Nutritionally balanced diet formulations for control and test diets	Compositional analyses were not performed on the test and control substances to confirm that test and control diets had similar nutrient content and were nutritionally balanced.	Ewen & Pusztai (1999)
Description of study design, methods and other details sufficient to facilitate comprehension and interpretation	Inadequate information was provided on the source of animals used, age, sex, animal husbandry practices followed, collection, and evaluation of biological samples to confirm that the procedures followed met accepted practices.	Ermakova (2007), Ewen & Pusztai (1999), Séralini et al. (2012)
Statistical analyses and study interpretation
Use of appropriate statistical methods for the design of the study	Statistical methods were sometimes not provided in sufficient detail to confirm if they were conducted appropriately for the data that were collected; statistical methods were documented, but were not appropriate. Estimates of statistical power were based on inappropriate analyses and magnitudes of differences.	de Vendômois et al. (2009), Ewen & Pusztai (1999), Malatesta et al. (2003, 2005), Séralini et al. (2007, 2012)
Appropriate interpretation of statistical analyses	Statistical differences were not considered in the context of the normal range for the test species, including data from historical and/or concurrent reference controls; the toxicological relevance of the difference was not considered (i.e., the reported finding is not known to be associated with adverse changes). Observed differences were not evaluated in the context of the entire data collected to determine if changes in a given parameter could be correlated with changes in related parameters.	de Vendômois et al. (2009), Ewen & Pusztai (1999), Kiliç & Akay (2008), Malatesta et al. (2002a, 2002b, 2003, 2005), Séralini et al. (2007, 2012), Carman et al (2013)
Adequate numbers of animals or test samples collected to be able to make meaningful comparisons between test and control groups	Too few animals/group were used to make meaningful comparisons; tissue sampling did not follow acceptable guidelines and was too limited to provide an accurate assessment of what was occurring in the organ being examined.	Ermakova (2007), Malatesta et al. (2002a, 2002b, 2003, 2005, 2008)
Study publication and availability
Publication of studies in peer-reviewed journals	Circumvention of the peer-review process removes a level of review that may contribute to ensuring that WF studies are appropriately designed and interpreted.	Ermakova (2007), Velimirov et al. (2008)

GM, genetically modified; WF, whole food.

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