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July 2001 Charge / Questions to the SAP

June 28, 2001

FIFRA SAP WEB SITE: https://www.epa.gov/scipoly/sap/

Assessment of Additional Scientific Information Concerning StarLinkT Corn

Exposure to Cry9C in Human Food:

At the November 2000 SAP meeting, EPA provided an exposure assessment for StarLink corn that was based on then available information. Specifically, EPA prepared an upper bound estimate of potential exposure to Cry9C protein as the consequence of the presence of StarLink in the human food supply. EPA used data on the consumption of food containing or made from corn, and data measuring the levels of Cry9C protein in corn grain. Notably, EPA assumed that the level of StarLink in finished foods was not reduced by processing of grain or by subsequent cooking.

EPA's exposure calculations also used information on the extent of planting of StarLink in 1999 and 2000, as well as information on grain handling practices, to produce high end estimates of the amount of StarLink corn that could be commingled with non-StarLink corn. These estimates did not take into account the various steps that have been taken since the fall of 2000 to limit the amount of Cry9C protein that could be present in the human diet. These steps include:

In addition, since November, more refined data and new analyses have been developed to estimate the amount of the Cry9C protein that would be available in finished food products. A new analytical method has been developed by EnviroLogix that is capable of measuring the levels of Cry9C protein in finished foods. Aventis has also provided data on the impact of processing and cooking on the levels of Cry9C protein in various types of finished foods made from corn. Aventis has employed these data to produce new estimates of potential exposure to Cry9C protein. Finally, EPA has prepared its own estimates of exposure to Cry9C protein in human foods made from the wet milling of corn.

1. The performance of the EnviroLogix ELISA test for the determination of Cry9C protein processed corn-based foods was evaluated using eight types of corn-based foods in an interlaboratory study involving seven laboratories in the United States. The FDA report on the multi-laboratory validation of the new analytical method indicated that the method is applicable to the determination of the Cry9C protein in eight types of corn-based products at levels equal to or greater than 2 ppb. In light of this assessment, please comment on the utility of this method for assessing the concentration of Cry9C protein in processed corn based foods and specifically the use by Aventis of this method for their revised exposure estimates.

2. EPA has prepared a paper evaluating the impact of wet milling on the levels of Cry9C protein in human food products. Please comment on the levels of exposure to the Cry9C protein in the human diet likely to be encountered in food products as consequence of using human food fractions made from the wet milling of corn.

3. At the November 2000 meeting, the SAP reviewed the exposure assessment submitted by Aventis which estimated the possible levels of Cry9C protein that could be consumed by people eating food products made from corn if the corn contained any Cry9C protein. Aventis has submitted a revised exposure assessment which takes into account the new data estimating the levels of Cry9C protein that could survive processing, and thus occur in corn-based food products. Please comment on whether this updated assessment fairly and accurately depicts the levels to which consumers may be exposed.

4. Assuming the measures taken to limit the amount of StarLink in the human food supply are continued and with your knowledge of how corn and food products made with corn move through the channels of trade, please comment on the duration and levels of detectable amounts (at ppb) of the Cry9C protein that are expected to be in the human food supply from: a) StarLink TM corn planted in 1998 through 2000; and b) From other domestic sources that might contain the Cry9C protein, e.g., volunteer StarLink TM corn and non-StarLinkTM varieties that express the Cry9C protein.

Allergenic Hazard and Risk:

The potential for the Cry9C protein to elicit an allergic response has been the single human health endpoint of concern for Starlink corn. In its December, 2000 report to the Agency, the Scientific Advisory Panel (SAP) concluded that "... there is a medium likelihood that the Cry9C protein is a potential allergen..." The SAP went further to recommend a number of follow- up activities that would allow for a better informed characterization of the potential allergenic risk. These activities included: (1) collection of data on the presence of specific antibodies in individuals either who claim to have experienced adverse effects after consuming food that might have contained the Cry9C protein or who have significant occupational exposure to Starlink corn or corn products, and (2) monitoring of reports from the medical community for individuals who claim to have experienced adverse effects either after consuming food that might have been made from Starlink corn or from occupational exposure to Starlink corn.

5. FDA and CDC have been working together to investigate the adverse event reports submitted to FDA by people who claim to have had an allergic response following the ingestion of genetically modified corn products. One aspect of the investigation was to determine if these people were exposed and displayed an allergic response by the formation of serum antibodies to the foreign Cry9C protein. An FDA laboratory developed an enzyme linked immunosorbent assay (ELISA) method to detect these antibodies in the sera of the people who were potentially affected. Although there were no known Cry9C-allergic human serum samples to serve as true positive controls, the assay was able to detect reactions in sera from goats that had been purposefully sensitized against the Cry9C protein, and also to detect reactions to certain human allergens (e.g., cat, grass, peanut) in sera from humans with known allergies to these allergens.

Some of the individuals who claimed to have experienced an allergic reaction to the Cry9C protein following the ingestion of corn-based products kept samples of (or could identify) the products they ingested. FDA tested these foods for the presence of StarlinkTM corn. StarlinkTM corn DNA has not been detected in 10 of 11 food samples analyzed using the PCR method. The other sample of food, which tested positive using the PCR method, was not from the consumer's actual product, but from a different lot of the same product collected by FDA from a grocery store. In addition, the pCry9C protein was not detected is 9 (including the food sample that tested positive using the PCR method) of the 10 samples tested with the EnvioLogix ELISA method. One of the 10 samples tested using the EnviroLogix method was inconclusive. There was no testing of one food sample using the EnviroLogix method because there was not enough of the remaining sample to conduct the test.

Given these circumstances, please comment on:

a) the ability of the test to detect Cry9C-specific antibodies;

b) the criteria used to designate test results as positive or negative, and the significance of positive and negative results obtained using this test;

c) the ability of the test to either identify or eliminate Cry9C as a potential cause of the allergic symptoms reported; and

d) the usefulness of the test, along with other information gathered in the FDA and CDC investigation, in evaluating whether an individual has experienced an allergic reaction to the Cry9C protein.

6. In the December, 2000 SAP report, after reviewing the information then available concerning the Cry9C protein, the Panel concluded that "... there is a medium likelihood that the Cry9C protein is a potential allergen based on the biochemical properties of the Cry9C protein itself..." The same report went on to state that "Given the current state of knowledge regarding allergens and the uncertainties of ascertaining the exact amounts of Cry9C in the food chain, this approach [collecting data on the presence of specific antibodies in individuals claiming exposure to Cry9C in food products] could provide 'hard evidence' as opposed to speculation on the question at hand." Since then, additional information concerning the potential allergenicity of the Cry9C protein has become available, including the FDA/CDC report issued on June 11, 2001, which provides information on the presence of Cry9C-specific antibodies in individuals claiming to have experienced an allergic reaction after eating corn-based foods. In light of the available information, what is the current Panel's view on the previous finding of that there is a "medium likelihood' that Cry9C protein is a human allergen? Please comment specifically on whether and how that view is significantly affected by your consideration of the June 11, 2001 reports from FDA and CDC.

7. In its December 1, 2000, report, the Panel concluded that "...the likely levels of Cry9C protein in the U.S. diet provide sufficient evidence of a low probability of allergenicity in the exposed population."

a) In light of the new information on the levels of Cry9C protein in the diet and the other available information concerning potential allergenicity, please comment on the overall probability that the likely levels in the US diet of Cry9C protein are sufficient to cause significant allergic reactions in a major identifiable subgroup of the exposed population. To the extent permitted by available information, please characterize the current level of potential risk in terms of the proportion of the population likely to be affected and the nature and severity of potential effects.

b) If you conclude that it is probable that the expected levels of Cry9C protein are sufficient to cause significant allergic reactions in a major identifiable subgroup of the exposed population, please identify a level of Cry9C protein below which you would not expect significant reactions to occur in a major identifiable subgroup of the exposed population.

c) Based on your responses to questions 7 a) and 7 b), do you conclude that there appears to be a maximum level of Cry9C protein for which, if that level were found in corn grain and foods made from such grain, there would be a reasonable scientific certainty that exposure would not be harmful to public health? Please explain your answer.

Possible Need for Additional Data and Additional Public Health Measures:

8. In its December 2000 report, the SAP concluded "...the Agency should place ...priority on monitoring of reports from the medical community. The Panel felt that the medical community should be informed of the investigation into the allergenicity of Cry9C in corn products." Approximately 8 months have passed since that original recommendation and, given the materials that have been discussed at today's meeting, we ask the Panel to please comment on the value of implementing a program involving the medical community intended to detect instances in which individuals experienced allergic reactions to the ingestion of Cry9C protein in food. If the Panel still regards such a program as potentially valuable, then please comment on the scope and design of such a program.

9. In its December 2000 report, the SAP identified additional types of information that could improve EPA's ability to assess the potential allergenic risk to humans from Cry9C protein in the food supply. In response to the Panel recommendations, Aventis Crop Science and the Federal government have developed new information on the Cry9C protein which has been presented to the Panel today. Given all the information that we presently have, please characterize generally the adequacy of the existing scientific database to evaluate the allergenic risk of Cry9C and identify any additional information that would be feasible to generate and would be likely to change significantly the current assessment of the allergenic risk to humans from the Cry9C protein in the food supply.

10. From a public health perspective, please identify other measures, if any, beyond those currently being implemented that you consider feasible and necessary to reduce the likelihood that people would experience allergic reactions from ingestion of food containing Cry9C protein.

11. Are there any other comments on the science of this issue that EPA should consider or that the SAP panel would like to address?

FIFRA SCIENTIFIC ADVISORY PANEL (SAP)
OPEN MEETING July 17-18, 2001

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