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2-Plants: FoE-US criticizes EPA's risk assessment of Bt plant pesticides

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TITLE:  Some see problems with renewals of Bt crop registrations
SOURCE: Farm News from Cropchoice, USA,
DATE:   October 1, 2001

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Some see problems with renewals of Bt crop registrations

(Oct. 1, 2001 - CropChoice opinion) - The following are excerpts from the 
report, "Final Comments for Submission to the Environmental Protection 
Agency Docket No. OOP-00678B: Concerning the Revised Risks and Benefits 
Sections for Bacillus thuringiensis Plant-Pesticides," by Bill Freese of 
the environmental group Friends of the Earth. The comments discuss various 
problems with Bt crops and why the Environmental Protection Agency should 
not re-register five varieties of these transgenic crops, which produce 
insecticidal proteins from the soil bacterium Bacillus thuringiensis. The 
EPA had approved transgenic StarLink corn, which is a Bt variety, only for 
livestock feed and industrial purposes, because of concerns that it was 
allergenic to humans. Despite that, StarLink found its way into the human 
food supply, forcing costly recalls, financial nightmares for farmers and 
grain handlers, and a steep cut in corn purchases from major export 
customers such as Japan.

To see the complete comments that Friends of the Earth submitted to the 
EPA, visit

Key Findings

Health Assessment of Bt Crops

- The EPA has failed to establish and/or apply standards for the health 
assessment of the genetically engineered Bt crops being considered for 
registration: three varieties of Bt corn, one each of cotton and potatoes 
(Sections 3 & 12)

- While the EPA is supposed to evaluate three parameters of allergenicity - 
digestive stability, resistance to heat and structural similarity to known 
allergens or toxins - the Agency has either failed to demand that companies 
submit corresponding studies, despite the lapse of 5 years since the 
original registrations, or the data submitted are of poor quality (Section 
3, Table 2)

  - Amino acid sequence homology: The EPA has collected virtually no data 
on potential similarities between the structure of Bt proteins and the 
structures of known allergens and toxins, even though all experts agree 
that this simple test should always be carried out on all genetically 
engineered foods, and even the EPA considers it to be "required" data 
(Section 4)

  - Digestive stability: Two studies submitted to the EPA demonstrate that 
the Bt corn protein, Cry1Ab, exhibits digestive stability similar to that 
of StarLink cornÕs Cry9C protein. This was one of the key findings that led 
the EPA to reject StarLink for human consumption (Section 6)

  - Heat stability: Cry1Ab also exhibits stability to heat comparable to 
that of StarLink Cry9C. The EPA has accepted substandard tests for other Bt 
crops that fail to assess the parameter of interest - the degree to which 
the Bt protein is degraded by heat (Section 5)

Deficient Product Characterization

- Many of the studies submitted by companies were conducted on Bt proteins 
from different crop lines, representing distinct transformation events, 
than the one registered, leading to the dubious practice of "data 
bridging." (Section 9)

- Much of the safety testing was performed on truncated versions of 
bacterial surrogate proteins rather than the full-length, plant-produced Bt 
proteins people are actually exposed to. Studies supposedly demonstrating 
the equivalence of bacterial surrogate proteins to their plant-produced 
counterparts for the purpose of safety testing do not meet the standards 
set by EPAÕs scientific advisors, and so should not be accepted (Section 10)

- The EPA relies unduly on data generated with Bt microbial pesticides, 
which differ in significant ways from the Bt crop-produced proteins 
(Sections 8 & 11)

- MonsantoÕs Yieldgard corn is the result of a transformation gone awry. 
While Monsanto intended to insert the full-length cry1Ab gene, apparently 
only a fragment was incorporated, for reasons unknown. Monsanto has had 
difficulty even detecting the 92 kD protein supposedly produced by this 
gene fragment. Yieldgard also lacks the foreign genes for the herbicide-
resistance trait that were supposed to be inserted and were "apparently 
lost during the development of the MON 810 line." (Sections 1 and 8.2)

- The Agency has no data confirming the removal of the ampicillin 
resistance gene from the DNA used to transform SyngentaÕs Bt 11 corn 
(Section 1)

Procedural Violations

- The EPA has largely ignored the recommendations of its scientific 
advisors (SAP Bt Plant-Pesticides, SAP Mammalian Toxicity), contrary to the 
AgencyÕs claim that it has considered them (Sections 1 & 10)

- The EPAÕs Biopesticides Registration Action Document shows no evidence 
that the EPA has considered "the most current health and ecological data" 
or "all available scientific information on Bt products," the supposed 
purpose of this re-assessment

- "Required" data that should have been collected and carefully evaluated 
before these crops were originally registered are still missing/deficient 
despite the lapse of five years, and the EPA appears poised to compound 
this error by re-registering the crops, perhaps without time limit, in the 
absence of these "required" data (Section 3)

Data Apparently Not Considered

- A 1999 study by Bernstein et al partly sponsored by the EPA suggesting 
that the Bt proteins Cry1Ab and Cry1Ac can elicit antibody (IgE) responses 
consistent with allergic reactions in farm-workers has apparently not been 
considered, despite the explicit recommendation by SAP Bt Plant-Pesticides 
that the Agency make use of serological agents developed in the course of 
this study to conduct "clinical assessment of exposed individuals" (Section 

- A series of 4 studies on mice dated 1999 and 2000 by Vazquez et al 
showing that Cry1Ac is a potent immunogen, increases antibody responses to 
other antigens, and binds to surface proteins in the mouse small intestine 
have also apparently been ignored. One of these studies was recommended by 
SAP Bt Plant-Pesticides for consideration by the EPA (Section 11)

- The Agency has had evidence since the 1994 that Bt protoxins differ 
immunologically from the truncated proteins used for testing purposes, yet 
apparently has not followed up on this important finding (Section 8)

- Evidence that the toxic portion of Cry1A proteins can have a different 3-
D conformation depending on whether it is part of the protoxin or in its 
free state, and that DNA structurally associated with the protoxin is 
released during the proteolysis process that generates the toxic fragment 
from the protoxin has also gone unconsidered (Section 8).

Executive Summary

Over the past decade, the scientific and medical communities have become 
increasingly concerned about the potential of genetically engineered (GE) 
foods to cause allergies. GE foods produce "novel" proteins that are often 
new to the human diet and are most often derived from bacteria. Allergies 
are triggered by aberrant immune system responses, which often occur when a 
susceptible person is exposed to a new food (or food protein). It is 
thought that food allergies afflict 2-2.5% of adults and 6-8% of children 
(SAP StarLink II, p. 11; Sampson 1999), or about 8 million Americans 
children (based on US Census data). Food allergies are becoming more 
common, for reasons still unknown. Because GE foods introduce novel 
proteins, and the process of acquiring allergies is still poorly 
understood, a growing number of experts recommend labeling of genetically 
engineered foods and monitoring for potential allergic reactions after 
market introduction.

The Environmental Protection Agency is presently considering whether or not 
to re-register five genetically engineered Bt crops - three varieties of Bt 
corn and one each of cotton and potatoes - which produce insecticidal 
proteins derived from a soil bacterium known as Bacillus thuringiensis. 
Concern about the potential allergenicity of one variety of Bt corn, 
StarLink, led the EPA to deny approval of this crop for human food use. 
After the food supply nevertheless became contaminated with StarLink, a 
panel of experts that included some of the nationÕs leading allergists 
advised the EPA that it was impossible to establish a threshold below which 
the StarLink protein, Cry9C, could be considered safe for human 
consumption. It was for this reason that the EPA refused to approve a 
petition by StarLinkÕs developer, Aventis CropScience, to allow even an 
extremely low level of Cry9C residues in the food supply.

In examining studies submitted to the EPA and recommendations by the 
AgencyÕs scientific advisors, Friends of the Earth has found evidence that 
the bacterial-derived insecticidal proteins produced by other Bt crop 
varieties either possess properties similar to those of Cry9C, or have not 
been assessed for the same. These allergenic properties include digestive 
stability, resistance to heat, and structural similarity to known allergens 
(or toxins).

In particular, studies conducted by Aventis CropScience and Dr. Hubert 
Noteborn demonstrate that the Cry1Ab toxin produced by the Bt corn 
varieties registered to Monsanto and Syngenta exhibit digestive stability 
that is similar to StarLinkÕs Cry9C toxin. NotebornÕs study also shows 
Cry1Ab and Cry9C have comparable resistance to breakdown by heat. The 
Agency has apparently not collected any data on potential similarities 
between the Bt proteins and known allergens or toxins, aside perhaps from 
limited data on Bt potatoes (see Table 2).

Additional concerns are raised by the poor quality of the studies conducted 
by the registrant companies. In many cases, these studies were conducted on 
Bt proteins from different crop lines than the one that was registered. In 
addition, the bulk of safety testing was performed on truncated versions of 
bacterial surrogate proteins rather than the full-length plant-produced Bt 
proteins that people are actually exposed to. This use of surrogates for 
testing purposes is a controversial practice, and is supposed to be 
permitted only if the bacterial and plant-produced versions are shown to be 
equivalent. The so-called "test substance equivalence" studies submitted by 
registrants do not meet the standards recommended by EPAÕs expert advisors. 
Failure to establish such equivalence in the case of the StarLink protein, 
Cry9C, was a major reason the EPA refused to permit even low levels of this 
protein in the food supply.

In addition, several of the Bt crops did not turn out as planned by the 
registrants, casting doubt on their ability to control the crude "gene gun" 
transformation (i.e. engineering) process. MonsantoÕs Yieldgard corn, for 
example, apparently contains only a fragment of the gene that was supposed 
to be inserted, due to an unexplained failure in the transformation 
process. The company has had difficulty even detecting the protein actually 
produced by this gene fragment, and has conducted its testing instead on 
the portion of this protein that is resistant to trypsin. Yieldgard corn 
also lacks the foreign gene for the herbicide-resistance trait that was 
supposed to be inserted, again for reasons unknown.

Both the registrants and the EPA make invalid comparisons between Bt 
microbial pesticides (i.e. Bt sprays) and the plant-produced Bt proteins to 
support their contention that the latter are safe, despite the fact that 
there are a number of important differences between the native Bt proteins 
and the modified versions produced in crops.

Finally, the EPA has apparently failed to consider important evidence 
demonstrating that Cry1Ab elicits antibody (IgE) responses consistent with 
an allergic response in farm-workers, as well as other studies 
demonstrating that the closely related Cry1Ac induces a potent antibody 
response in mice, increases the antibody response to other antigens, and 
binds to surface proteins on the mouse small intestine.

The seriously deficient data submitted by registrants raise questions about 
the potential health impacts of their Bt crops. The EPAÕs flaccid 
acceptance of poorly conducted corporate studies, and its apparent 
unwillingness to demand "required" data, casts doubt on the entire 
regulatory process, which appears to be unduly biased towards approval of 
Bt crops in the absence of critical data.

The unanswered questions with respect to the potential health impacts of Bt 
crops take on added significance in the context of an increasing incidence 
of food allergy, whose causes remain unknown. The EPA is urged to conduct a 
thorough and rigorous re-assessment of the Bt crops being considered for re-
registration by demanding that missing data be supplied, requiring that 
deficient studies be repeated under proper conditions, and giving full 
consideration to the recommendations of its expert scientific advisors. Re-
registration should not even be considered until complete and accurate data 
have been collected and carefully evaluated.

1.	Introduction

The EPAÕs stated objective in its reassessment of Bt crops is "to assure 
that the decisions on the renewal of these registrations are based on the 
most current health and ecological data." The reassessment is supposed to 
take account of "all available scientific information on Bt products," 
giving particular consideration to recommendations by the EPAÕs Scientific 
Advisory Panels (e.g. SAP Bt Plant-Pesticides 2000, SAP Mammalian Toxicity 
2000) as well as the National Academy of SciencesÕ in-depth review of Bt 
crops (NAS 2000) (EPA BRAD 2001, p. I1, my emphasis).

A thorough-going reassessment is badly needed for several reasons. First, 
genetically engineered Bt crops are still a relative newcomer on the 
agricultural scene, having been approved for commercial planting barely 
more than half a decade ago. Since that time, there has been a great deal 
of research on these crops which should be considered before a decision is 
made on whether to allow their continued cultivation. Second, the science 
of genetic engineering is still primitive. The process of transgene 
insertion is crude and haphazard. As a result, even plant developers often 
lack complete data on their transgenic products. Pleiotropic (i.e. 
unexpected) effects are more common than once imagined, and often remain 
undiscovered for years, by which time the crop may have come to be 
cultivated on tens of millions of acres.

For example, since their introduction in 1994, evidence has accumulated 
that Roundup Ready (RR) soybeans, by far the most widely planted 
genetically engineered crop, have lower phytoestrogen levels (Lappe et al 
1999); depressed root development, nodulation and nitrogen fixation; lower 
levels of aromatic amino acids; and lower average yields than their 
conventional counterparts (Benbrook 2001). In addition, the original 
promise of reduced herbicide use has proven false; in fact, cultivation of 
Roundup Ready soybeans is associated with application of greater amounts of 
herbicide, on average, than their conventional counterparts (Ibid). These 
hard facts - lower yields and increased herbicide use - contrast sharply 
with vague biotech industry promises that future GE crops will somehow 
"feed the world" and reduce agricultural chemical use. Finally, fragments 
of DNA undetected at the time of original registration were recently 
discovered in MonsantoÕs product, five years after the crop was first 
commercialized. Two of these fragments, 72 and 250 base pairs in length, 
appear to be partial copies of the CP4 EPSPS gene which lends RR soybeans 
their herbicide resistant trait (Monsanto RR Soybeans 2000). More recently, 
a Belgian team reported that a 534 base pair segment of DNA flanking the 
previously undetected 250 bp fragment does not match soybean genomic DNA, 
as expected, and suggested that it could be scrambled plant DNA or DNA from 
an unknown source (Windels et al 2001).

Scientists are only now beginning to unravel the molecular basis of the 
pleiotropic effects mentioned above. In order to do so, thorough and 
accurate product characterization data are essential. For this reason, one 
could argue that no genetically engineered crop should be in the fields or 
on the market until it has been completely and accurately characterized at 
the molecular level. At the very least, it seems hard to argue with the 
notion that regulatory authorities should demand the best information 
possible with the most modern techniques that are available. Some of the 
improved techniques employed by Monsanto and the Belgian team in obtaining 
more accurate characterization of RR soybeans (e.g. genome walking, cosmid 
library construction and northern blot analysis) (Monsanto RR Soybeans 
2000, p. 4) have apparently not been applied to the Bt products being 
considered for reregistration.

For instance, the Agency is set to re-register SyngentaÕs Bt 11 corn 
despite lack of data confirming removal of the ampicillin resistance gene 
from the transforming DNA (EPA BRAD 2001, p. IIA5). In the case of 
MonsantoÕs Bt corn, the EPA seems satisfied with the conclusion that: 
"These genes which confer glyphosate tolerance were apparently lost during 
the development of the MON 810 line…" (Ibid, p. IIA7). In addition, the 
Agency appears to be untroubled by the failed transformation event by which 
only a portion of the intended full-length cry1Ab gene sequence was 
actually incorporated into the genome of MON 810 corn, despite MonsantoÕs 
apparent difficulty in detecting the protein encoded by this unintended 
fragment (Ibid, p. IIA7; see Section 9.2).

The very prevalence of genetically engineered Bt crops is still another 
reason for a strict and thorough reassessment. Even if impacts on health 
and the environment prove to be minor, it must not be forgotten that we are 
dealing with crops planted on tens of millions of acres, to which large 
numbers of people are exposed. To take a concrete example: If StarLinkÕs 
Cry9C protein is shown to be even a rare allergen, affecting just a tiny 
percentage of the population, the likelihood that tens of millions of 
people have consumed tainted corn products (Friends of the Earth 2001, pp. 
14-15) suggests that a large number of people may have been affected. And 
if StarLink, which was never planted on more than 0.4% of total U.S. corn 
acreage, can spread so widely in the food system, it is reasonable to 
assume that the other Bt corn varieties, which constitute roughly 20% of 
U.S. corn production, have been consumed by nearly every American for 
several years now.


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