LEDA at Harvard Law
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BIOPHARMING :
UNIQUE CHALLENGES & POLICY PROPOSALS
Karen Guo
Class of 2004
April 2004
Third Year Paper
Professor Hutt
Food & Drug Law
Biopharming is the genetic engineering of plants to produce novel pharmaceuticals and useful industrial compounds. It has the potential to provide revolutionary benefits, but it also raises a host of daunting challenges. Part II provides background information on the technology of biopharming, including the types of products, host plants, and harvesting procedures involved. Part III describes the dramatic benefits of large-scale, flexible, and inexpensive production of life-saving pharmaceuticals and useful industrial compounds. Part IV explains the grave risks associated with the “escape” of biopharm material outside its intended scope, and the potential environmental, health, and economic damage that may result. Part V describes the U.S. federal regulatory regime’s current efforts at controlling the dangers of biopharming, but notes its inadequacy with respect to post-market oversight. Part VI examines the legal liability system as an auxiliary mechanism for post-market oversight, but acknowledges that litigation has its own shortcomings. And finally, Part VII explores policy proposals for the creation of a comprehensive solution to minimize the risks of biopharming so that its benefits can be fully realized.
Biopharming is the genetic engineering of plants to produce novel pharmaceuticals and useful industrial compounds. As the “second wave” of agricultural biotechnology, it is quite a recent phenomenon and presents a fascinating array of benefits and risks. It offers the promise of revolutionizing the cost structure of medicine, providing an abundant source of life-saving pharmaceuticals at much lower prices to millions of needy patients worldwide. Yet, biopharming also poses dramatic challenges to the environment, human health, the food supply, and export markets. Currently, multiple U.S. federal agencies regulate biopharming, but the regulatory system may be inadequate to control the dangers of biopharming. Thus, injured parties may resort to the legal liability system for relief. In the long run, however, the best way to reap the benefits of biopharming while minimizing its risks may lie in a combination of additional measures, including regulatory changes, self-regulation, and encouraging international acceptance of biopharming.
Humans have harvested medicine from plants since virtually the dawn of time. Farmers have also cross-bred different plant varieties for centuries untold. Biopharming, however, takes these two traditions one giant step forward. Rather than harvesting naturally occurring, traditional medicines from plants, it involves genetically engineering plants to produce novel, cutting-edge pharmaceuticals. And instead of cross-breeding different varieties within the same species, it crosses over species lines to introduce foreign traits into plants.
Biopharming can be thought of as the “second wave” of agricultural biotechnology. The “first wave” began decades ago and involves expanding production yields for food crops, increasing their pest resistance, conferring immunity to weed killers, and enhancing the quality of fruits and vegetables.[1] The “second wave” of biopharming is a far more recent development, emerging at the turn of this millennium. It involves genetically engineering plants into “factories” to produce foreign substances that are medically, scientifically, or industrially useful. In other words, it focuses on the production of “plant-made pharmaceuticals”(PMPs) and “plant-made industrial compounds”(PMIs), rather than traditional food or feed.
Biopharming can produce PMPs for innovative treatments of Alzheimer’s disease, cancer, cystic fibrosis, diabetes, heart disease, HIV, kidney diseases, and many others.[2] It can also produce PMIs such as industrial enzymes and chemicals for use in various industrial processes. Specifically, the range of potential PMPs and PMIs covers both primary products and derived products. Primary products are proteins and include antibodies (immunoglobulins), antigens (vaccines), enzymes (diagnostic, therapeutic, cosmetic), enzyme inhibitors, structural proteins (peptides, hormones), and anti-disease agents.[3] Derived products are mostly non-protein molecules and include bio-plastics, vitamins, co-factors, nutraceuticals, secondary plant metabolites (phenolics, glucosinolates, tannins, starches, sugars, fragrances, flavors, alkaloids), and fibers.[4]
Companies are already using plants to produce the following products: (1) antibodies to treat cancer, heart disease, and other chronic conditions, (2) vaccines for hepatitis B, measles, and traveler’s diarrhea, (3) blood clotters like aprotinin, (4) blood thinners, (5) growth hormones, (6) contraceptives, and (7) industrial enzymes such as trypsin for use in various industrial processes, including the manufacture of human health products.[5]
Various countries, including U.S., Canada, and France, have been exploring biopharming. Currently in the U.S., at least 400 biopharm products are in the research pipeline, with more than 300 having been tested in open-air field trials throughout the country.[6] In 2002, for instance, the USDA’s Animal and Plant Health Inspection Service (APHIS) issued permits for such field trials on 120 acres nationwide.[7] Some PMPs are already being sold, such as ProdiGene Inc.’s TrypZean™ and AproliZean™, recombinant trypsin and aprotinin produced in corn.[8] Many others are in the clinical trials phase of the FDA’s drug approval process.[9]
For the first time in April 2004, biopharm crops will be grown commercially on a significant scale in California; Ventria Bioscience, a company based in Sacramento, plans to grow two varieties of genetically engineered rice. The rice will produce lactoferrin and lysozyme, chemicals that fight infection. Ventria plans to sell them for use in oral rehydration products to treat severe diarrhea. It will initially begin with 52.6 acres, and within a few years it aims to expand to 405 acres.[10]
Various types of host plants have been used for biopharming. Corn is by far the most popular candidate, but others include alfalfa, barley, canola, carrots, corn, lettuce, potatoes, rice, safflower, soybean, tobacco, tomatoes, and wheat.[11] Due to the long history of agricultural cultivation of such plants, biopharm scientists can utilize the wealth of information about their physiology and ecology (e.g., pollination, genetics, seed dormancy, weediness potential).
As for the part of the host plants used for gene expression, seeds are the most popular choice. Seeds provide ease of storage, distribution, and delivery because proteins stored in seeds become dessicated and remain intact for long periods of time. In fact, they can be stored for at least a year with no decrease in pharmaceutical activity.[12] This explains why grain and oilseed crops that produce large quantities of seeds (e.g., corn, rice, wheat, soybeans) are commonly used for biopharming. Increasingly, however, scientists are also exploring the possibility of gene expression in other parts of plants, such as the leaves.
Once PMPs and PMIs are produced in plants, they must be harvested. Harvesting usually involves grinding up the crop, extracting the PMP or PMI, and then purifying it in the laboratory.[13] Note that in the past, certain companies such as ProdiGene proposed the “dual-use” of biopharm crops, extracting the PMP or PMI and then selling the remainder for use as food or animal feed. But such proposals will unlikely be enacted due to the risk of drug or chemical residue in food and feed.[14]
Initially, scientists had hoped to simplify the harvesting process by producing “edible vaccines,” or “medicinal foods,” via biopharming. Theoretically, PMPs could be grown, stored, and distributed as seeds, tubers, or fruits, so that patients could directly consume plants in raw form to obtain the necessary drugs.[15] Administering a drug would be as easy as eating a banana. Pharmaceuticals would not need to be extracted and purified into a pill, nor would they have to be administered by needle. This would dramatically reduce the costs of storage, transportation and delivery. In fact, such edible vaccines could revolutionize healthcare in poor and developing countries, making immunization much cheaper and thus widely available.
Unfortunately, edible vaccines have not turned out as successful as envisioned, for a variety of factors. First, determining the correct dose is difficult. Orally ingested pharmaceuticals will be subject to digestive enzymes and stomach acids. Higher concentrations of vaccine must be engineered into plants to make up for the fact that only a portion survives degradation and reaches the immune system. Estimates suggest that 10-100 times as much edible vaccine as would be needed for injection.[16] Moreover, the harshness of the digestive system varies among individuals and also over time. This variability means that the optimal dosage for one person may be too much or little for another.
Second, even if a standardized “correct dose” could be determined, scientists have encountered difficulties in achieving consistent PMP levels in plants. Many factors affect such levels, including plant health, degree of ripening, length of growing season, weather conditions, light levels, pest infestation, and the genetic background of the host plants. Naturally, more variability is introduced when biopharm plants are grown in open-air fields. But even under strictly controlled greenhouse conditions, it is hard to achieve consistent PMP levels. Furthermore, fruits and vegetables vary in size. Hence, even if scientists could achieve consistency in terms of “x mg/g” of plant tissue, it is virtually impossible to achieve consistency in terms of “x mg/piece” of fruit or vegetable.
Third, it is also difficult to engineer sufficiently high pharmaceutical levels in plants. Many of the plants that are popular foods and hence attractive options for edible vaccines (e.g., apples, bananas, tomatoes) do not typically produce high levels of protein. Hence, it is hard to engineer the high PMP levels that are necessary for drug efficacy. This is especially difficult because much more vaccine is required for oral ingestion than an injection, as explained earlier.
Fourth, a potentially significant obstacle is oral tolerance. This is the process whereby the body comes to accept an ingested protein, rather than forming antibodies in response. Oral tolerance is usually beneficial because the body develops tolerance to food proteins (i.e., thereby preventing allergies). But this process could render edible vaccines ineffective because no immune system response would be elicited. Partial oral tolerance has already been found in mice fed potatoes engineered to produce a vaccine for traveler’s diarrhea caused by Norwalk virus.[17] Thus, oral tolerance could be a “very big handicap” until scientists discover how to avoid it.[18]
Together, these difficulties make edible vaccines unfeasible. Thus, PMPs can most likely only be extracted from plants and processed into pill, powder, or liquid form, thereby increasing the costs of storage, transportation, and delivery.[19]
Biopharming was originally hailed as a boon for everyday farmers looking for more profitable crops to increase their meager profit margins. For instance, the Colorado Farm Bureau supported the idea of allowing Meristem Therapeutics of France and ProdiGene of Texas to conduct biopharming field tests in Colorado, stating that it would provide a new market for drought-battered farmers.[20] And in Iowa, Governor Tom Vilsack also envisioned a major role in biopharming for the state’s numerous farmers, especially in light of Iowa’s prime location in the Corn Belt (i.e., the Midwestern region covering states such as Illinois and Iowa).[21] Increasingly, however, people are realizing that biopharming presents an opportunity for only an elite group of meticulous farmers who must be trained and legally bind themselves to carefully following stewardship procedures.[22]
Biopharming has the revolutionary potential of becoming the new millennium’s optimal production system for pharmaceuticals and industrial compounds. As mentioned earlier, it offers increased ease of storage and transportation, but that is just one of a long list of promising benefits. Other benefits include higher quality pharmaceuticals, increased production capacity, greater production flexibility, and potential cost savings.
Currently, many pharmaceuticals are obtained either by: (1) extraction from animal or human tissue, or more commonly, (2) fermentation in transgenic systems like animal cell, bacterial, and yeast cultures.[23] Biopharming, however, may be a more effective and preferable method of production. That is because plants better than microorganisms at assembling complex molecules, including human proteins and antibodies, in their proper configurations.[24] Using plants also prevents the transmission of animal pathogens to humans, which may occur when proteins are extracted from animals like cows or produced in cell cultures.[25] Plant diseases, in contrast, do not infect humans.[26]
Unfortunately, conventional methods of extraction and fermentation simply cannot provide sufficient production capacity. The pharmaceutical industry, both in the U.S. and worldwide, is developing more protein-based pharmaceuticals than standard culture systems can produce.[27] Thus, the global demand for such pharmaceuticals far exceeds the industry’s current production capability. Unless alternative production systems are used, promising new treatments may never make it to the market.[28] Fortunately, biopharming may be the solution to this capacity shortage. For instance, for some products, a full year’s supply of substrate can be produced from as few as 2,000 acres.[29]
Furthermore, as discussed below, biopharming offers dramatically lower production costs, which in turn provides great flexibility when adjustments in production are necessary. Since far less capital is necessary to double the acreage of a biopharm field than to double the capacity of a bricks-and-mortar factory, companies can adjust production more swiftly and accurately to meet fluctuating demand.[30]
The current production method of fermentation is also prohibitively expensive.[31] It requires large and highly sterile fermentation complexes, which often cost $500 million or more to construct and operate.[33] As a result, pharmaceuticals are often impossibly expensive and thousands if not millions of people worldwide cannot benefit from these life-saving innovations. Conventional production methods simply cannot deliver pharmaceuticals at prices affordable to the vast majority of patients in the world. Though AIDS drugs are the prototype of prohibitively expensive pharmaceuticals, innovative drugs for a wide diseases ranging from arthritis to tuberculosis are also unaffordable.[34] Each year, about 1.6 million unvaccinated children die of diseases for which vaccines exist.[35]
To illustrate, consider hepatitis as an example. Hepatitis is one of the most common diseases in the world. Hepatitis B affects more than one third of the world, and hepatitis C affects at least 170 million people globally. Among those afflicted with hepatitis C, many suffer from severe liver cirrhosis, for which there is currently no available vaccine. Theoretically, the cost per patient for annual treatment with insulin-like growth factor I (IGF-I) would be an astronomical $18 million, for 600 mg (1.4-2 mg per day) at $30,000 per mg. Even the more reasonable cost of $26,000 per year for interferon therapy for viral hepatitis is still far beyond the means of the vast majority of the world. Considering the fact that almost one billion people in the world make less than one U.S. dollar per day, they sadly remain untreated for debilitating or even fatal diseases.[36]
But using plants as “drug factories” offers the potential of dramatically reduced production costs, and hence, a revolution in the pricing structure of many pharmaceuticals. The production inputs for biopharming are relatively inexpensive; the primary raw materials are water and carbon dioxide, and the energy for production via photosynthesis comes free from the sun.[37] There is a pre-existing agricultural infrastructure that can be adapted to biopharming, and relatively little capital investment is necessary.[38] Furthermore, the potentially massive scale of agricultural production of pharmaceuticals makes biopharming an exceedingly attractive alternative.[39] Plants can be grown by the acre, producing higher yields with far less maintenance and far less cost. For instance, Epicyte Pharmaceutical Inc. of San Diego projected that with 200 acres of corn it could make the same amount of pharmaceuticals produced by a $400-million factory per year.[40] ProdiGene also claimed that one $2.50 bushel of corn produces as much avidin as a $1,000 ton of eggs.[41] Some estimates suggest that costs could be cut in half.[42] Other estimates are even more optimistic, suggesting that the production cost of a transgenic drug could drop from $50-$100/g using fermentation, to $12-$15/g using biopharming.[43] Some even predict that production costs can be 10- to 50-fold lower if proteins were produced by plants rather than by E. coli fermentation.[44]
Note, however, that these production cost reductions might actually not be realized in practice. Factors that could make biopharming expensive or downright unfeasible are: (1) difficulties in purification, (2) the cost of containment measures, (3) the desire of biopharm companies to recoup investment costs, and (4) the possible internalization of currently externalized costs.
First, purification of PMPS and PMIs may be difficult because whole plants typically contain a larger number of extraneous compounds than animal cell, bacterial, and yeast cultures. Tobacco plants, for instance, contain about 4,000 constituents. Second, a variety of containment measures may be necessary to prevent biopharm “escape.” The use of extensive physical (detasseling, tassel bagging, dedicated machinery), spatial (buffer zones, “grower regions”), temporal (atypical growing seasons), and bioconfinement (male sterility, terminator genes, suicide genes) measures can be quite costly. Third, even if production costs are low, the ultimate sale prices charged by biopharm companies may be considerably higher. This is because companies will want to recoup large sunk costs of investments in production, extraction, purification, and containment techniques. For instance, the research chemical avidin, a currently commercialized PMI, is priced twice as high as the traditional version extracted from eggs.[45]
And fourth, perhaps most importantly, the production costs of biopharming are artificially low due to the externalization of the costs of the “escape” of biopharm material outside its intended scope of use. As discussed further below, this externalization results from suboptimal enforcement of federal regulations, as well as the failure to hold biopharm companies legally liable for such escape. If these costs were internalized, biopharming could become far less economically feasible, if at all.[46]
The greatest risk of biopharming is the “escape” of biopharm material outside its intended scope of use. Such escape can occur in multiple ways: (1) transgenic “gene flow” of genetically engineered biopharm characteristics into wild or cultivated relatives via cross-pollination, (2) “reseeding” of the biopharm crops themselves outside delimited fields, (3) inadvertent exposure of the public through physical commingling of biopharm material with the food supply, (4) inadvertent exposure of the public through other channels, and (5) excessive exposure of workers to biopharm materials.[47]
Of particular concern to many is the first possibility of “gene flow.” Gene flow has always occurred naturally through cross-pollination, and also as the result of deliberate breeding by traditional methods. It is thus not a recent phenomenon. But genetic engineering goes beyond traditional breeding because it crosses species lines, thus raising concerns about possible adverse ecological and health consequences.
While the StarLink episode did not specifically involve biopharming, it is a prime example of the “escape” of GM material and the devastating consequences that ensue. The StarLink incident involved corn genetically engineered to produce its own insecticide, Cry9C. EPA had approved the corn solely for animal feed, not human consumption, because tests suggested that Cry9C could be a human allergen. Despite the use of containment measures, in September 2000 StarLink corn was discovered in corn-based food products. Though StarLink was grown on less than 0.4% of U.S. corn acreage in 1999, it subsequently appeared in over 430 million bushels of corn. To make things worse, the group that discovered it was not the government, but a consumer group (Genetically Engineered Food Alert).
Needless to say, this incident triggered a public uproar. The food industry had to endure the pain of massive recalls of more than 300 brands of taco shells, corn bread, and other processed foods. Corn traders also feared for their export markets. And naturally, environmentalists and consumers were also greatly alarmed. Many of these interest groups blamed the U.S. regulatory system for failing to prevent the StarLink disaster, and expressed demands for stricter government regulations of biotechnology.
StarLink proved to be a billion-dollar debacle. It spawned at least twenty-seven class action lawsuits in six states against the company that commercialized StarLink, Aventis CropScience USA.[48] Many of these lawsuits were consolidated, under multi-district litigation procedures, before U.S. district Court Judge James B. Moran in Chicago. In the settlement that followed, Aventis ended up paying hundreds of millions to farmers in crop buyback programs. U.S. taxpayers also probably shouldered a $20 million tax burden to buy contaminated seed stocks from seed distributors.[49] For years after it was first detected, StarLink turned up in shipments to major U.S. trading partners like Canada and Japan.[50] And even to this day, more than three years and millions of dollars later, traces of StarLink genes continue to appear in 1% of corn submitted by growers and grain handlers for testing.[51] Fortunately, StarLink corn turned out to be relatively harmless and did not end up significantly endangering any lives. But its economic toll was tremendous.
In the aftermath of StarLink, EPA did announce that it would no longer approve the registration of pesticidal traits in GM plants unless the altered plants were also approved for human consumption. Thus, this regulatory change should prevent future StarLink-like disasters involving GM crops with pesticidal traits. Even if contamination occurs, all pesticide-producing GM crops would already have been approved for human food use.[52] But this EPA regulation has no effect on biopharm crops engineered to produce PMPs and PMIs. To this day, APHIS has not issued any comparable regulation restricting approval of biopharm crops to only cases where the altered plants are approved for human consumption. Thus, many fear that the biopharm equivalent of StarLink could occur in the future, with potentially more devastating consequences.
After StarLink, another debacle occurred in 2002. This time, biopharm contamination was specifically involved. ProdiGene had planted biopharm corn in Nebraska to produce an anti-diarrheal (E. coli ) vaccine for pigs. After the crop failed, ProdiGene destroyed the plants, plowed the field, and allowed a farmer to plant soybean crops in the same field. Contamination resulted because ProdiGene did not ensure that all the corn seeds were removed from the field after the harvest. These lingering seeds sprouted into “volunteer plants,” especially since the soybean farmer had failed to use adequate weed control to prevent this volunteer growth.[53] During three separate inspections, APHIS discovered a small number of biopharm cornstalks growing among the soybeans. Despite explicit warnings by APHIS, the farmer apparently did not fix the situation because the cornstalk-contaminated soybeans were harvested and aggregated with a 500,000 bushel shipment.[54] Furthermore, a similar violation of ProdiGene’s APHIS-granted field test permit occurred in Iowa and also involved volunteer corn.[55]
In response to the contamination, APHIS quarantined and then destroyed 500,000 bushels of contaminated soybeans.[56] The fields tainted by drifting pollen were also torched to the ground.[57] APHIS accused ProdiGene of mishandling its biopharm corn and fined it $250,000. Though ProdiGene did not admit fault, it agreed to pay $3 million in fines and for cleaning up the fields.[58] It is fair to say that the ProdiGene incident was detected quickly and resolved swiftly before any significant damage resulted to the environment or human health. However, it drew attention to the fact that companies entering the new field of biopharming may have insufficient prior experience with complying with federal regulations.[59] Similar compliance infractions may very well happen again in the future, and we might not be as lucky next time.
Generally, regardless of whether the “escape” of biopharm material occurs via gene flow or any of the four other mechanisms listed earlier, such escape has many grave ramifications. Indeed, it raises a sobering host of environmental, health, and economic concerns.
Since transgenic gene flow introduces novel traits into cross-pollinated offspring, it modifies the gene pool for that species.[60] Theoretically, the cross-pollination of biopharm crops with wild or cultivated relatives could weaken the fitness of the result offspring. Alternatively, the exact opposite could occur; it could actually improve the general fitness of the offspring. But that might not necessarily be a desired result, if the resulting offspring is an undesirable variety. For instance, consider how this phenomenon has arisen in the “first wave” of agricultural biotechnology. Specifically, there have been cases of: (1) weedkiller-resistant crops crossbreeding with wild weeds and producing new variants of hard-to-kill “super weeds,” (2) and gene flow from GM canola resulting in the spontaneous emergence of canola that possess three different traits for herbicide resistance, making it more difficult for farmers to control “volunteer canola.”[61] Analogous problems could result with biopharming, if cross-pollination gives rise to robust but undesirable new varieties with drug-producing traits. As of now, it remains unclear whether the effect comes out positive or negative on balance. [62]
Gene pool modification via gene flow affects not only the cross-pollinated species itself, but also the entire ecosystem. That is, biodiversity is potentially threatened.[63] Currently, the potential effects of PMPs and PMIs on the environment and various ecosystems are largely unknown. Up until now, there was no need to know. That is, pharmaceuticals and industrial compounds were generally tested only for their traditionally limited spheres of use – patients and industrial activities, respectively. Hence, scientists never had to inquire into the effect of plant-made antibiotics on scavenging fungi in forest soils, for instance.[64] But now, with the advent of biopharming, antibiotic-producing plants might actually end up in unintended environments like forests, if the pollen of biopharm crops contaminates their wild relatives miles away. PMPs and PMIs could very well wreak havoc on delicate ecosystems via gene flow.
Furthermore, even in the absence of gene flow, biopharm material could still escape through other mechanisms into the natural ecosystem and wreak havoc. First of all, plants that produce significant levels of biologically active proteins could affect the viability of soil organisms.[65] Such adverse effects could occur both during the growing season and post-harvest, when roots and plant residues may be left behind in the soil and water. [66] Granted, soil bacteria and fungi contain protein-degrading protease enzymes, so with a little moisture, they may be able to degrade pharmaceutical proteins that enter the soil into harmless amino acids.[67] Even when proteins adhere to clay particles, as has been observed for the Bt toxin protein, they are neither biologically available nor significantly mobile under natural moisture conditions.[68] Nevertheless, some scientists still warn that biopharm proteins could potentially persist in the soil for months.[69] Furthermore, non-protein PMPs and PMIs may not be as biodegradable as protein PMPs, and thus may pose a greater threat to soil organisms.
And secondly, PMPs and PMIs could also endanger wildlife or livestock that inadvertently eat biopharm crops or drink water with plant residues.[70] Many pharmaceuticals are environmentally persistent, lipophilic molecules that can pass through cellular membranes. These physiochemical properties may cause them to bioaccumulate in living organisms and hurt non-target organisms.[71] For instance, avidin can kill or chronically impair 26 species of insects, while aprotinin and other digestion-inhibiting enzymes shorten the lives of honeybees.[72]
Mere exposure to biopharm material could pose a threat to human health. Indeed, pharmacological doses can be obtained from dust exposure, via inhalation or dermal absorption. And the fact that biopharm plants are deliberately engineered to produce high concentrations of PMPs and PMIs increases the risk of such exposure. To illustrate, consider the fact that in corn, certain drugs exist at total levels of roughly two parts in 1,000 (2 mg/g) and extractable levels of half that (1 mg/g). Since the average ear of corn has 480 to 700 kernels (16 to 20 kernel rows, 30 to 35 kernels per row) and four kernels of corn roughly constitute a gram, each ear of corn averages between 120 to 175 grams and a mere 6 to 9 ears can contain 1mg of a potent drug.[73] Hence, employees working in rows and rows of biopharm corn can be exposed to nontrivial levels of drugs, even through mere dust exposure.
Those endangered include not only on-site workers handling the biopharm plants, but also off-site individuals in the general public. One can imagine off-site contamination resulting from various scenarios, including: (1) production-batch sheets used in the fields and brought into administrative offices for filing, and (2) work clothing being brought home for laundering, thereby exposing workers’ families.[74]
When PMPs are used for their intended purpose, as prescription or OTC drugs, they will likely be safe because the FDA will already have verified their safety and efficacy during the drug approval process. That is, the FDA will have approved only those biopharm drugs that are as stable as those produced in traditional cell cultures, and also effective in eliciting immune responses in humans. Moreover, these drugs will be administered only under carefully controlled conditions that ensure purity and potency (i.e., correct dosage). They will also be given only to patients who need the drug and for whom the drug is suitable; some drugs, for instance, are inappropriate for pregnant women, young children, and the elderly.
But if humans inadvertently ingest biopharm products that accidentally enter the food supply, significant dangers may exist. As opposed to GM food crops, GM biopharm crops are not tested for human consumption at all because they are not supposed to be consumed except in the limited situation described above.[75]
Granted, a subset of PMPs may not pose a threat when inadvertently ingested because they are rapidly digestible in the stomach or intestine. Immunoglobulins are an example, and in fact, we commonly ingest non-therapeutic doses of immunoglobulins when we consume meat. That is why immunoglobulins typically have to be injected or intravenously administered in order to deliver a therapeutic dose to patients. Furthermore, many antibodies and vaccines are designed for delivery directly to the bloodstream anyway. Even if they are inadvertently ingested, as long as they are readily dissolved in the digestive system and delivered to the bloodstream, they may not actually pose a great risk.[76]
However, other PMPs that are not rapidly digestible may pose significant health risks. First, a general concern is that since plants process protein differently than animals or humans, a medical reaction could ensue if the body considers a plant-produced “human” protein a foreign body. Although biopharm proteins are “natural” in that they also naturally occur in animals and humans and are even often coded for using human gene material, the process of glycosylation complicates matters. During glycosylation, plants attach to proteins certain plant-specific sugar groups that are more likely to elicit reactions than the mammalian glycosylation pattern of proteins cultured from animal cells.[77] The reaction could be as severe as a life-threatening anaphylactic shock.[78]
Second, even if oral ingestion of a certain PMP or PMI is generally harmless for most people, it may cause an allergy or other medical reaction in a subset of the population. Trypsin and antitrypsin, for instance, are corn-grown industrial enzymes that are known allergens. Aprotinin is a blood clotter that can cause pancreatic disease in animals and possibly humans, and the research chemical avidin causes a vitamin deficiency. Growth factors such as erythropoietin may be harmful via inhalation, ingestion, or skin absorption.[79]
Third, even if oral ingestion of a certain PMP is safe for all humans if taken in small amounts, many biopharm plants are engineered to produce not small but high quantities of PMPs or PMIs. Even if PMPs elicit beneficial responses at low concentrations, they may be toxic at higher ones.[80] After all, the dose makes the poison. Thus, just a few kernels of biopharm corn could contain enough therapeutic protein to make inadvertent consumption unsafe.[81] This danger grows as scientists are striving to produce ever-higher concentrations of PMPs and PMIs in biopharm crops.[82]
Fourth, inadvertently consumed PMPs could result in oral tolerance and render certain pharmaceuticals ineffective. For instance, vaccines secreted through plant roots could end up in groundwater, and hence drinking water, and babies who grow up drinking such water may develop oral tolerance. Alternatively, oral tolerance could move up the food chain. That is, wild relatives that are genetically contaminated by biopharm crops may start producing an antibiotic that ultimately lose its efficacy as the wild plants are consumed over time by unsuspecting animals, and then by humans who eat the animals.[83]
To this day, the degree to which inadvertent consumption of biopharm material poses the human health risks discussed above remains the subject of considerable scientific debate. However, the mere potentiality of such risks has dramatic economic ramifications for all food-related industries, domestic and international. Multi-billion dollar interests are at stake, and can only be preserved if biopharm crops are strictly isolated from the food supply. Biopharm contamination of any type of food crop (i.e., conventional or organic) would almost certainly destroy its marketability. And once food is rendered unmarketable, the producer (i.e., the farmer who grew the crop, or the food company who manufactured the processed food) cannot recoup prior investments of sunken production costs.
The economic loss described above is a threat to all types of food producers, both conventional and organic. But note that the specialty market of organic foods may be dealt an especially hard blow, due to higher sunk costs associated with organic farming and organic food processing. Organic farmers must invest in natural fertilizers, natural pest control agents, and labor-intensive methods, which produce lower yields and cost more than conventional methods. They intend to recoup these higher upfront costs by charging an “organic” premium for their crops. For instance, organic corn may fetch $0.80 per ear, as opposed to $0.60 per ear for conventional corn. However, if biopharm contamination renders the value of both types of corn to $0 per ear, the organic farmer faces a greater loss than the conventional farmer, in terms of unrecouped investment. This example also illustrates how biopharm contamination is more damaging than general GM contamination; whereas contamination by GM corn would only decrease the value of organic corn from $0.80 to $0.60 per ear (i.e., since many U.S. conventional crops are GM crops anyways), contamination by biopharm corn would result in complete unmarketability.
Biopharm contamination threatens the domestic food supply, including both the U.S. commodity crop market and the U.S. processed foods industry. First, in the U.S. commodity crop market, farmers growing conventional or organic corn, soybean, and other food crops are quite vulnerable to biopharm contamination. Even if a particular farmer’s crops are not contaminated, he could still experience decreased sales and depressed prices due to a general decline of consumer confidence in the U.S. commodity crop market. For instance, Ventria’s announcement of its plan to commercially grow biopharm rice for the first time in California greatly alarmed California’s rice growers.[84]
Second, in the U.S. processed foods industry, contamination by biopharm material could result in expensive product recalls and long-lasting damage to brand names. Massive paranoia could arise if consumers were to discover PMPs and PMIs in the food supply. The short-term cost of immediate recalls would be tremendous, and the long-term loss of consumer confidence (i.e., goodwill) could be even more staggering. Even if inadvertent consumption of biopharm material does not turn out to actually pose a significant health risk, the food industry is extremely risk-averse. The industry is quite wary of any controversy, after having endured the expensive recalls of L-tryptophan in the 1990s and StarLink in this decade, both of which still lack conclusive scientific proof of harm.[85] On top of expensive recalls, there is also the threat of legal liability. Consumers claiming to have suffered illness or injury after consuming contaminated food could sue food companies. Food processors remember all too clearly the StarLink class action lawsuit in Chicago, in which several food processors (e.g., Kraft Foods Co., Aztec Foods Inc., and Mission Foods Co.) shared with Aventis the burden of a multi-million settlement.[86]
In fact, the processed food industry is so alarmed that it has appealed to federal agencies for greater protection of the integrity of the food supply. For instance, after the ProdiGene scare, the Grocery Manufacturers of America (GMA) demanded that food crops cease to be used for biopharming. It insisted that biopharming should be limited to non-food crops, at least until “science and federal regulations” could fully prevent contamination of the food supply.[87] Furthermore, even after APHIS shifted to a stricter permit system in 2003 (described below), GMA nevertheless declared the need for an even more “stringent and comprehensive” regulatory system for biopharming.[88] Joined with 10 other U.S. processed food industry trade associations representing multiple sectors, GMA emphasized the need to protect the food supply. Though the GMA voiced support for biopharming as a cost-effective method to produce vital medicines and vaccines, it urged APHIS and the FDA to implement a comprehensive regulatory system to replace what it viewed as the current “piecemeal” regulation of biopharming.[89]
Biopharm contamination could also destroy export markets. Currently, foreign countries have enacted relatively little regulation regarding biopharming since the technology is still at its incipiency. But in the near future, once biopharm crops are commercially and widely grown in the U.S., the risk of biopharm contamination in U.S. food exports will undoubtedly trigger regulatory reactions abroad. Just as the European Union (EU), Japan, and other countries have imposed zero tolerance policies for many unapproved GM food crops, they will almost certainly impose zero tolerance on biopharm crops. This means that if any trace of biopharm material is found, shipments will be rejected upon arrival.[90] A tremendous amount is at stake because of the size of these export markets. For instance, the U.S.-European agricultural trade was valued at $6.4 billion in 2001.[91] Corn exports alone amount to as much as $1 billion, all of which is endangered by the possibility of biopharm contamination.
As foreshadowing of what the future likely holds for biopharming, consider the extreme anxiety with which foreign countries currently approach GM foods. Take, for instance, the EU’s current ban on most GM foods. Unlike Americans, Europeans are far less receptive to the idea of GM foods. Much of this is rooted in the “precautionary principle,” the idea that whenever an activity potentially threatens human health or the environment, precautionary measures should be taken even if causal relationships are “not fully established scientifically.”[92] In other words, nothing should be done until it has been proven safe. Largely due to this mentality, Europeans markets have been essentially closed to new GM foods for the past 4 years, under a de facto moratorium since June 1999.[93] Specifically, as of February 2003, there were 18 GM food products approved in the EU, but the de facto moratorium has left at least 13 applications pending indefinitely. This moratorium is on both the production of such crops within the EU, as well as the import of such crops in the region. Thus, U.S. food exports containing any trace of unapproved GM varieties are currently banned from the EU, as well as other nations following the EU’s lead. In the future, the EU could very likely impose a similar “zero tolerance” regime on biopharm crops.
Currently, U.S. trade lawyers are challenging the EU’s de facto moratorium as a “trade barrier” under the World Trade Organization. Yet, even if U.S. were to prevail in this suit, at most the EU would only lift its ban on GM food crops. It is less likely that the EU—or other countries, for that matter—would go so far as to approve biopharm crops, which are not meant for human consumption at all and thus fall into a different, more dangerous subcategory of GM crops. But even in the unlikely event that foreign governments would be so generous as to establish non-zero tolerances (e.g., 1% in EU, 5% in Japan, etc.), it would be unrealistic to assume that mere compliance with these government thresholds would secure export markets. In actual practice, most large European and Japanese food companies have zero tolerance for GM food ingredients, let alone non-food biopharm material. This zero tolerance standard is dictated by consumer preferences and by the conservative nature of international food trading.[94] Thus for all intensive purposes, it is safe to assume that biopharm material will be subject to an effective, even if unofficial, zero tolerance standard abroad. The only way this could change is if international consumer preferences changed in the future.
Furthermore, there is also the possibility that foreign countries may even impose a stricter, “less-than-zero” tolerance standard. This possibility is especially salient given the adoption and ratification of the Cartagena Protocol on Biosafety. This international protocol was adopted by more than 130 countries on January 2000, and entered into force in September 2003. Its objective is to contribute to the safe transfer, handling, and use of living modified organisms that cross international borders, and has been widely regarded as international validation of the precautionary approach. In particular, one of its requirements is that shipments of GM commodities (e.g., corn, soybeans) that are intended for direct use as food, feed, or for procession must be accompanied by documentation stating that such shipments "may contain" living modified organisms and are "not intended for intentional introduction into the environment.”[95]
As a result, commentators predict that countries may apply the protocol to refuse any shipment of commodity crops that “may contain” traces of unapproved GM crops, presumably including biopharm ones.[96] Importing nations might require U.S. exporters to state “to a moral and legal certainty” that there “could not possibly be” any unapproved varieties. If U.S. exporters cannot make such strong assurances, the countries might refuse shipments without even actually testing them for the presence of unapproved GM material, including biopharm material. Moreover, regulatory authorities may even be required by law to assume that biopharm material may be present at some low percentage, and thus reject all U.S. shipments. This would amount to a “less-than-zero” tolerance regime because the mere presence of biopharm crops in the U.S. could figuratively “taint” all U.S. food exports, even if they are not actually physically contaminated.[97]
Given the virtual certainty of a zero tolerance regime, or even worse, the possibility of a less-than-zero tolerance regime, the consequences for U.S. exports will be devastating. To predict how biopharm contamination will destroy export markets, consider how contamination by GM food crops has already damaged these markets. In the U.S., exporters have lost billions of dollars since the introduction of GM crops in 1996. Before 1996, U.S. corn farmers made a profit of $1.4 billion. But in 2002, they actually lost $12 billion. That was because prices in 2002 were at their lowest for 30 years, down from $3 to $1.30 a bushel. In fact, U.S. corn exports to the EU have fallen from millions of metric tons to almost zero since the introduction of GM Bt corn. In the soybean market, soy farmers lost billions when prices fell by more than $2 a bushel, due at least partly to Monsanto’s introduction of the herbicide-resistant “Roundup Ready” soybean. And in the potato industry, U.S. exporters lost 37% of the large Japanese potato market when traces of GM potatoes were found in snacks exported to Japan. The U.S. Potato Board even had to institute an expensive program to remove all GM potatoes entirely.[98]
Moreover, as the StarLink debacle illustrated, export markets can be single-handedly destroyed by merely one careless biotech company. According to Dr. Robert Wisner, an Iowa State University Extension economist, commingling of StarLink corn in the U.S. corn supply was at least partially responsible for a 7% drop in U.S. corn exports a year after in 2001. Corn exports to Japan, Korea, and Taiwan dropped especially low that year, down 20% from the previous year. Granted, exports to Asia were also influenced by other factors, including competition from Chinese corn and the disruption of the Japanese livestock industry (and hence its demand for animal feed) by the discovery of mad cow disease in Japan. Yet StarLink corn was definitely one of the factors causing this dramatic 20% drop, particularly since it was banned in Japan for fear that it was a potential human allergen. Overall, the Asian market is quite vital to U.S. corn exports, as Japan, Korea, and Taiwan import more than half of U.S. corn sold abroad. Given the demonstrated anxiety of the Asian market towards contamination of corn exports by a potential allergen, one can only imagine the fear that would ensue from news of corn exports contaminated by drugs and industrial chemicals.[99] Hence, all it would take is a biopharm equivalent of the StarLink incident to devastate export markets for a major commodity crop like corn or soybean.
As illustrated above, biopharming offers both revolutionary benefits and daunting risks. Thus, much careful thought must be invested in deciding how to approach this controversial technology. On the one hand, we must carefully control it so as to avoid environmental, health, and economic disaster. But on the other hand, we should avoid stifling a technology that offers such dramatic benefits to medicine and industry. Our aim should be to find a means to “peaceful coexistence,” so that we can reap the benefits of biopharming while minimizing its risks. As a first step in this process, consider the U.S. government’s current efforts at regulation of this technology.
Under the U.S. Coordinated Framework for the Regulation of Biotechnology, several federal agencies—APHIS, FDA, EPA, and OSHA—have regulatory responsibility over different aspects of biopharming.[100] To understand the agencies’ respective and often overlapping responsibilities, it is useful to divide the process of biopharming a PMP into at least five stages: (1) the first stage of preliminary, experimental field testing to determine whether the genetically modified host plant can successfully produce the PMP, (2) the second stage of pre-market approval, (3) the third stage of full-scale commercial production in the fields, (4) the fourth stage of extraction and purification into finalized form in laboratories, and (5) the last stage of post-production waste disposal.
The USDA’s APHIS has primary authority for regulating the growth of biopharm plants during both the first stage of experimental field testing and the third stage of full-scale commercial production in the fields. The FDA’s responsibility spans from the second through the last stage (thereby overlapping with APHIS in the third stage) because the FDA is responsible for the entire manufacturing process of all pharmaceuticals.[101] The EPA is responsible for the regulation of pesticides, as well as the protection of the environment from manufacturing processes, under authority of the Toxic Substances Control Act, the Clean Air Act, and the Clean Water Act. Hence, the EPA can become involved if either: (1) any biopharm plants contain pest-protection or herbicide-tolerance characters that might require a new use pattern for an herbicide (and thus a product label change), or (2) any of the five biopharming stages raises environmental concerns related to pest-protection characters or pesticides. And finally, OSHA may step in to require risk mitigation measures if worker safety is threatened by excessive exposure to PMPs and PMIs during any of the five stages.[102]
Naturally, there is a certain degree of overlap in the regulatory responsibilities of these federal agencies. Thus, the agencies strive for coordination through interagency deliberations. For instance, APHIS maintains close and regular discussions with the FDA, especially the FDA’s Center for Food Safety and Applied Nutrition (CFSAN) and the FDA Commissioner’s Office.[103] Since APHIS and the FDA are responsible for the bulk of biopharming regulation, this paper focuses on these two regulatory bodies.
As mentioned earlier, the FDA oversees the second through the last stage of the biopharming process. During the second stage, biopharm companies seeking pre-market approval must prove to the FDA the safety and efficacy of their PMP through animal testing and clinical trials conducted under Good Laboratory Practice (GLP) standards. These GLP standards are designed to prevent fraud, audit data, and ensure that other scientists can replicate the submitted studies. During the third and fourth stages, the FDA requires biopharm companies to adhere to Good Manufacturing Practices (GMPs) to ensure product safety, purity, and potency via consistent manufacturing processes. And during the fifth and final stage, the FDA requires the safe disposal of biopharm waste products.
To clarify the application of its general drug regulations to the specific case of biopharming, the FDA released a draft document in September 2002 entitled “Guidance for Industry: Drugs, Biologics, and Medical Devices Derived from Bioengineered Plants for Use in Humans and Animals.” It provides recommendations on the use of GM plants or plant materials to produce biological products, including intermediates, protein drugs, medical devices, new animal drugs, and veterinary biologics.[104]
The USDA’s APHIS has primary authority for regulating the first stage of experimental biopharming. This is part of APHIS’ more general duty to regulate all agricultural biotechnology. Since 1987, it has monitored the field testing of more than 10,000 GM organisms and also overseen the deregulation of more than 60 GM products. In the past few years, the Bush administration has taken various measures to strengthen APHIS’ regulatory power. For instance, the Bush administration established a dedicated compliance and enforcement unit to ensure adherence to USDA regulations. It also created in 2002 the Biotechnology Regulatory Services (BRS) unit, to focus specifically on the constantly evolving policy issues of biotechnology.[105]
Under the authority of the Plant Protection Act, BRS oversees the importation and interstate movement of biopharm crops.[106] It also regulates the release of these entities into the environment (i.e., outside of greenhouses, laboratories, fermentors, and other contained facilities); open-air field testing falls within this category.[107] To engage in any of these activities, biopharm companies must apply for a permit from BRS in accordance with regulations in 7 C.F.R. §340.[108] To accomplish its mission, BRS engages not only in permit issuances, but also rulemaking and risk assessments.[109]
Prior to 2003, APHIS’ regulation of biopharming involved a notification process, a more expedited procedure, if PMPs or PMIs met certain safety and familiarity criteria. However, this notification process proved ineffective in preventing various non-compliance problems in 2002, such as the ProdiGene incident. In response to this, and also in anticipation of the future scale-up and commercialization of PMPs and PMIs, APHIS replaced the notification process with a field permit system in 2003. APHIS’ BRS first implemented this permit system for PMPs in March 2003, and then extended it to PMIs in August 2003.
Overall, the new permit system involves stricter requirements and a greater government role in enforcement than the old notification system. First, the required distances for buffer zones around biopharming fields have been increased.[110] For openly-pollinated corn, the required buffer zone has been doubled from half a mile to a mile. For detasseled corn, restrictions have also become stricter; buffer zones must be half a mile, and non-GM cornfields between half and one mile away must be planted at least 28 days before or after the biopharm corn.[111]
Second, the frequency of field trial inspections has also been increased. Under the old regime, APHIS typically conducted one or two inspections during the growing season, and a few more during the next growing season (i.e., to detect “volunteer plants” in post-biopharmed plots that had since returned to food crop production).[112] But under the new regime, the minimum is seven times—five times during the growing season and twice during the next growing season. In fact, APHIS inspection report forms identify specifically what inspectors are to examine during pre-planting, planting, mid-season, pre-harvest, harvest, and post-harvest inspections. These sheets also identify key events where compliance issues are most likely to arise, and list whom to contact so that appropriate officials can take remedial action immediately. Thus, the system is designed to have APHIS inspectors “look for the right things at the right times.” Moreover, while these inspections are timed with critical events during field testing, new requirements have also been imposed to facilitate ongoing auditing throughout each field test.[113]
Third, there are stricter regulations on conventional farming in post-biopharm fields. Whereas the old regime prohibited only the cultivation of edible corn in fields that had been used for biopharm corn within the previous year, the new regime requires explicit APHIS authorization before any food or feed crop can be grown in such fields. The purpose of this is to facilitate the detection and destruction of post-biopharming “volunteer plants” that sprout and commingle with food or feed crops grown in the same plot of land. For instance, APHIS prohibits the planting of weedy crops like soybeans during the year following biopharming because such crops will likely proliferate throughout the field and obscure volunteer plants that might sprout. “Cover crops,” however, can be cultivated during the year immediately following the final season of biopharming, in order to enrich the soil and prevent it from eroding. Such cover crops are not harvested, but typically plowed under or burned down with herbicide. Any type of cover crop can be chosen, as long as APHIS inspectors can still detect and destroy any volunteer plants.[114]
Fourth, separate planting, storage, and harvesting equipment must be set aside for biopharming. Although such equipment can be returned to general use in the future, they must be cleaned in accordance with extraordinary, costly procedures.
And finally, the permit system requires biopharm companies to include as part of their permit applications specific risk mitigation measures. These include: (1) identification, packaging, and segregation measures to prevent mixing, spillage, and dissemination of viable biopharm plant material, (2) secure greenhouse design that prevents pollen flow, both outside the greenhouse and inside to sexually compatible plants that might be growing in the same building, and (3) devitalization/disposal of biopharm plant material, once no longer in use or no longer authorized, by appropriate means (e.g., dry heat, steam heat, crushing, deep burial, chemical treatment).[115]
Furthermore, to ensure the effectiveness of field inspections, APHIS has poured resources into training and mapping technology. With respect to training, APHIS has instituted new training programs to equip its inspectors with the skills necessary keep pace with rapidly-evolving biotechnology. Its intensive training curriculum not only prepares inspectors to examine GM crops in general, but also is specifically focused on the inspection and auditing of biopharm field tests. APHIS’s BRS also recently hired a private consulting firm to provide specialized audit training to BRS personnel and inspectors who review compliance records. And as for technology, APHIS is currently considering the use of global positioning system equipment to help inspectors identify field test location coordinates with precision. This is reflective of APHIS’ continual efforts to improve documentation of field test inspections.[116]
APHIS’ BRS has also been evaluating and analyzing historical compliance data as part of an on-going program review. Granted, BRS has only had a short history since its creation in August 2002. APHIS, however, has had more than 16 years of experience in regulating agricultural biotechnology; as mentioned earlier, APHIS has overseen the field testing of more than 10,000 GM organisms and the deregulation of more than 60 GM products. This historical review is facilitating APHIS’ efforts to strengthen monitoring and enforcement. For instance, the analysis of compliance data is useful for the development of standard criteria for assigning enforcement actions whenever compliance issues emerge. [117]
To be sure, the existing regulatory structure does provide for a certain degree of environmental review. To minimize duplication, APHIS has primary responsibility over the review of environmental safety issues posed by field growth of biopharm plants, including National Environmental Policy Act (NEPA) assessments.[118] Since biopharm plants must be grown under APHIS permits, and since permits enabling field testing must be obtained prior to the submission of a product application, APHIS already has the responsibility of evaluating the potential environmental effects posed by growing biopharm plants in fields.[119]
And once PMPs and PMIs are extracted and purified, the environmental effects of the final product (as opposed to the raw biopharm plants) are addressed by NEPA assessments conducted by the regulatory agency responsible for the review and/or approval of the particular product. For instance, the FDA is responsible for human biologics, human drugs, and animal drugs that are derived from biopharm plants and intended for therapeutic, preventative, or diagnostic purposes.[120] Thus, the FDA is responsible for NEPA assessments of these specific products. In general, the NEPA analyses conducted by these respective agencies take into account APHIS’ earlier environmental reviews of the raw biopharm plants.[121]
Theoretically, these two stages of review—conducted on both raw biopharm plants and final products—should cover all environmental issues that EPA would be concerned about. However, it is unclear whether everything really works smoothly in practice. In a 2002 report, the National Academy of Science’s National Research Council (NRC) expressed concern over APHIS’ handling of environmental risks associated with GM plants (including biopharm crops), stating that APHIS should review potential environmental more carefully before approving the commercialization of novel GM crops.[122] And in November 2003, a coalition of advocacy groups filed suit in federal court in Honolulu, Hawaii, demanding that APHIS better regulate open-air field testing of biopharm crops in Hawaii and elsewhere in the U.S.[123] Among other things, the coalition pointed out that no environmental impact statement relating to the field testing had been prepared by APHIS or any other government agency, nor did any agency asses the potential risk posed to endangered species.[124]
To its credit, APHIS has recently acknowledged the need to pay greater attention to the environmental threat posed by biopharming.[125] On January 22, 2004, Agriculture Secretary Anne Veneman announced the APHIS’ intent to update and strengthen its biotechnology regulations on the importation, interstate movement, and environmental release of certain genetically engineered organisms. The first step in this process will be a comprehensive environmental impact statement to evaluate both current regulations and several potential changes. The purpose of this impact statement is to enable APHIS to base future regulatory changes on “sound science principles” and “mitigation of risks.” [126] It should assist APHIS in ensuring that its regulatory framework has both the rigor and flexibility to keep pace with the constant advances in biotechnology.
Despite the elaborateness of the current U.S. federal regulatory regime, it may still be inadequate to control the risks of biopharming. This is because although it focuses on “pre-market” approval of biopharm crops, it does not ensure much “post-market” oversight. Pre-market approval refers to deciding which biopharm crops or products can be safely released into the environment or marketplace (i.e., field testing or commercial production). In contrast, post-market oversight refers to monitoring them after they actually enter the environment or the marketplace. Post-market oversight is crucial because the “escape” of biopharm material is most likely to happen in the post-market stage—when the crop is in the field, or when PMPs or PMIs are being prepared and sold to consumers. Effective post-market oversight is thus necessary to decrease the environmental, health, and economic damage caused by such escape.[127]
Under the current regime, federal regulators focus most of their attention on pre-market approval. For instance, APHIS issues field permits based on its evaluation of which biopharm crops are safe for the environment and human health, and FDA approves PMPs based on safety and efficacy proven in clinical trials. Yet these agencies spend comparatively less time on post-market approval. In fact, the 2002 NRC report expressed concerned over the level of post-market surveillance that occurs after GM crops, including biopharm crops, have entered the environment or marketplace.[128]
Of course, the federal framework does include a certain degree of post-market oversight. APHIS inspectors do monitor field test sites for compliance infractions, and there is also a dedicated compliance and enforcement unit within the agency. Unfortunately, however, APHIS is simply too understaffed to adequately monitor all biopharm companies all the time. This essentially gives companies free reign to monitor themselves—or not. Ironically, the ProdiGene incident highlighted APHIS’ lack of enforcement manpower. Granted, the agency was successful in discovering the contaminated soybeans relatively early. Furthermore, as described earlier, APHIS’ response to ProdiGene was swift, decisive, and effective. In fact, the Agriculture Secretary Ann Veneman gave APHIS’ BRS the “Secretary’s Honor Award” in recognition of how well it handled the incident. However, APHIS officials themselves asserted that the agency’s effective policing in the ProdiGene incident was rather an anomaly. The truth was that APHIS had been watching ProdiGene with heightened scrutiny at the time because the company had been cited for several previous violations. In the absence of such unusually close surveillance, APHIS might very well not have detected the contamination. Though ProdiGene turned out to be a near-miss, there is no guarantee that similar incidents could not happen again.
Thus, even if improvements were made in federal regulatory post-market oversight, the effectiveness of such oversight would be limited by the government’s finite resources. To prevent future disasters, this gap in the federal regulatory system must be filled by other monitoring and enforcement mechanisms. One increasingly likely possibility is the legal liability system, considered in the following section.
By allowing for private causes of action, the legal liability system mobilizes everyday citizens—and hence the entire public—into private attorneys general. It thus effectively increases the overall “taskforce” for monitoring and enforcement, supplementing the limited inspection manpower of federal agencies.
Furthermore, the legal liability system also provides much-needed compensation to individuals when they are harmed by the “escape” of biopharm material. Such escape may occur when non-compliance is undetected by regulators. Indeed, it could occur even despite full compliance; natural forces like birds, bees, waters, and wind carry pollen for long distances, and according to a January 2004 NRC report, even the most advanced containment methods cannot ensure 100% containment of biopharm material.[129] Thus, escape is virtually inevitable. It is only a question of when and where. Once escape occurs, the costs of biopharming will be externalized to its victims, including conventional farmers, organic farmers, food processors, exporters, and persons in the general public who are accidentally exposed to or inadvertently consume biopharm material. Those who have suffered damage to their property or person will almost certainly resort to the legal liability system for relief. They will most likely sue the “biopharmers”—biopharm companies who develop biopharm crops, “elite” individual farmers they contract to grow these crops, or both. Other potential defendants include commodity traders, food processors, and exporters who sell food contaminated by biopharm material.
To predict what this biopharm litigation will be like, one can look to past and
current litigation involving GM contamination. For instance, consider the numerous StarLink-related lawsuits. As mentioned earlier, StarLink contamination triggered at least twenty-seven class action lawsuits in six states against Aventis, the company that commercialized StarLink.[130] Examples of these class action suits include Southview Farms v. Aventis CropScience USA Holding, Inc. , Mulholland v. Aventis Crop Science USA , and Mudd v. Aventis . [131] When many of these lawsuits were ultimately consolidated in a district court in Chicago, the plaintiffs’ claims of negligence, private nuisance, and public nuisance survived a motion to dismiss.[132] And in another class action lawsuit, this time in the eastern district of Missouri, thousands of corn and soybean farmers brought nuisance claims against Monsanto.[133] Even in Canada, organic farmers are suing Aventis and Monsanto for the GM contamination of their organic canola, basing their claims on trespass, nuisance, negligence, and pollution.[134]
As suggested by these GM contamination lawsuits, biopharm litigation will be similarly based on one or more of the following theories: (1) trespass, (2) negligence, (3) strict liability, (4) private nuisance, and (5) public nuisance. Let us consider each in turn.
A trespass is the actionable invasion of a possessor’s interest in the exclusive possession of land.[135] It can occur either when a defendant crosses the legal boundary of another’s land, or when he causes something to cross that boundary.[136] The physical invasion can be the result of intentional, negligent, or ultra hazardous conduct.[137]
In other words, even unintentional acts can cause a trespass if the defendant knew it would occur with “reasonable forseeability.”[138] Thus, even if the defendant biopharmer did not intend for biopharm pollen or seed to drift onto nearby farms, there would be a question of whether this happened with reasonable foreseeability. In defense, the biopharmer could argue that reasonable foreseeability was lacking because he had already taken all containment measures required by federal regulation, if not more. But the plaintiff farmer could counter that, despite such measures, gene flow was substantially certain to occur, since according to the 2004 NRC report, even the most advanced bioconfinement methods cannot prevent “escape” completely.
For a trespass claim to be successful, the following elements must be met: (1) invasion of the plaintiff’s possessory interest in property, (2) caused by an act of the defendant, (3) resulting in damages to the plaintiff. As for the first element of invasion, “the nature of the intruding element,” including its size and magnitude, is irrelevant. Substances as imperceptible as dust, smoke, gases, lead particles, waste particles, low-level radiation emissions, and even invisible fluoride compounds may constitute a trespass.[139] Thus, the fact that pollen is barely detectable by the naked eye, and seeds may also be tiny, will not prevent this first element of invasion from being met.
The second element of causation is a much tougher hurdle. First, the plaintiff must establish that he did not himself introduce the biopharm contamination onto his own land (e.g., inadvertently planting contaminated seed). Then, he must prove that the contaminating pollen or seed came from a particular defendant.[140] Modern technology (e.g., polymerase chain reaction testing) can identify unique gene sequences to determine precisely which biopharm crop variety was the source of contamination. Thus, the issue of proof is simplified if there is only one biopharmer nearby producing that specific variety.[141] The plaintiff need only prove that: (1) the defendant was producing the specific biopharm variety at the time contamination occurred, (2) that biopharm variety is a species that could have caused the contamination, and (3) atmospheric conditions like wind patterns would have permitted contamination to occur. But if there are multiple biopharmers nearby producing the same biopharm variety, the plaintiff must present circumstantial evidence such as: (1) expert witness testimony showing the potential drift range of the defendant’s crops, (2) evidence of the likely drift pattern in the given atmospheric conditions, and (3) evidence of the defendant’s growing practices or other conduct that would identify the defendant as the likely source of contamination.[142] However, in practice, it is quite difficult to prove a case with such circumstantial evidence. Thus, instead of suing individual biopharmers, plaintiff farmers may go up the chain of commerce and join together in class action suits against the biopharm company who provided the seeds to the individual farmers in the first place.[143]
The third element of actual damages must also be met. Since gene flow is a natural phenomenon, if pollen flow by itself gave rise to liability for trespass, all farmers could be liable for every pollen- or seed-producing crop they ever grow.[144] Thus, there must be more than a “de minimis” intrusion.[145] The plaintiff must show that biopharm pollen or seed produced by the defendant has damaged the plaintiff’s property. One way to prove damage is to show that the land has been rendered “unfit” for its prior purpose. For instance, in Martin v. Reynolds Metals Co ., there were actual damages because the emanation of fluoride compounds made the plaintiff’s land no longer suitable for grazing livestock.[146] Similarly, an organic farmer whose land loses its “organic certification” as a result of biopharm contamination can argue that actual damages occurred. But for organic farmers whose land has not lost organic certification, and also conventional farmers who never had such organic certification anyways, it is more difficult to argue that the one-time contamination has rendered their land unfit for its prior purpose (unless “volunteer plants” in subsequent seasons will likely contaminate subsequent harvests).
However, such farmers may still prove actual damages if their harvest (e.g., organic crops, conventional crops, certified seeds) were contaminated and thus rejected by the market. The USDA’s National Organic Program (NOP) has explicitly stated that organic standards are process-based and not zero tolerance, meaning that such standards are not necessarily violated by “the presence of a detectable residue of a product of excluded methods.”[147] Similarly, the standards set by the Association of Official Seed Certifying Agencies (AOSCA) for certified seed production are also process-based and not zero tolerance. [148] However, since federal regulators have declined to adopt non-zero tolerances for traces of biopharm material in food, what results is an effectively zero tolerance standard. This is reinforced by consumer preferences; no commodity trader, food processor, or layperson will want to buy conventional crops, certified seeds, or organic foods “laced with drugs.” Thus, the plaintiff can likely prove actual damages by pointing to his lost sales.
As for the calculation of the damages, the plaintiff can point to the method used in “trespassing bull cases.” For instance, in Fuchser v. Jacobsen , where a trespassing Angus bull impregnated the plaintiff’s purebred Hereford cow, the damages amounted to the difference in market value of the cow immediately before and after impregnation.[149] Similarly, as applied to biopharm contamination cases, the measure of damages should be the price differential between the original market price and the current market price, presumably zero if there is total consumer rejection.
Negligence is a fault-based claim, unlike strict liability. The fault arises from the defendant’s failure to take adequate precautions. According to §282 of the Restatement of Torts, negligence is conduct that “falls below the standard established by law” for the protection of others against “unreasonable risk of harm.”[150] Plaintiffs must prove four elements: (1) a duty of care owed by the defendant to the plaintiff, (2) a breach of that duty, (3) damages, and (4) causation (both factual and proximate) of the damages claimed.
Under the first element, a duty exists when there is a “foreseeable likelihood that particular acts or omissions will cause harm or injury.”[151] As discussed under trespass, there arguably is a foreseeable likelihood that biopharm material will “escape” and cause damage if precautions are not taken. Hence, biopharmers have a duty of care to use adequate containment measures. Exactly what this duty is may vary with the host plant. For instance, if some host plants are particularly prone to pollen flow (i.e., corn), weediness (i.e., soybean), or volunteer plants, extra precautions may be necessary.[152] Such precautions may be physical (detasseling, tassel bagging, dedicated machinery), spatial (buffer zones, “grower regions”), temporal (atypical growing seasons), and bioengineered (male sterility, terminator genes, suicide genes).
The second element of breach is proven by showing that the defendant did not take the reasonable precautions described above. The defendant may point out that he did in fact use certain containment measures, such as buffer zones. Nevertheless, the plaintiff may argue that such measures were insufficient. This is especially salient when the defendant failed to utilize certain measures that could easily have been incorporated. For instance, if bioconfinement via male sterility can be reasonably engineered into biopharm crops, the failure to do so may make the court more likely to find the defendant in breach of his duty.[153]
As for the third element of damages, the plaintiff may allege damages to his property and/or his person. The first category of damages is the same as those one would allege under trespass. That is, a conventional or organic farmer could sue the defendant for biopharm contamination of his crops and/or his land, thus rendering his crops unmarketable and/or his land unfit for its prior use. The second category of damages can be alleged by all persons (i.e., not just farmers), such as workers suffering from excessive exposure to biopharm materials, or people in the general public who inadvertently consumed biopharm material due to a contaminated food supply. Such allegations could be based on toxicity, allergic responses, or ill-effects to health caused by long-term exposure.
As for the fourth element of causation, the plaintiff must overcome difficulties of proof similar to those discussed under trespass. He must show that his injuries were directly and proximately caused by the defendant’s actions or lack thereof. The causal relation between negligent conduct and final harm may not be obvious to the ordinary layperson, especially in cases where the plaintiff claims damages to his person. And when the casual relation is not obvious, expert testimony “in the fields of chemistry, medical, veterinary and botanical science” may actually be “essential” to the determination of legal causation.[154] If such expert testimony is used, courts will likely require “proof to a reasonable degree of scientific certainty.”[155] Note, however, that in practice, defendants face considerable liability risk even in the absence of hard scientific evidence. For instance, when sued by consumers who inadvertently consumed StarLink-contaminated food, Aventis ended up shelling out millions in a settlement despite the fact that the CDC found no evidence that StarLink actually caused any allergic reactions.
Strict liability applies to abnormally dangerous activities and, unlike negligence, imposes liability without fault. Liability can attach even despite the exercise of utmost care. Examples of abnormally dangerous activities include “storing and using explosives, spraying pesticides, spilling toxic substances, allowing the escape of sewage, and allowing the escape of noxious or poisonous gases, fumes or vapors.”[156] If a court finds strict liability, the plaintiff need not show fault and is virtually guaranteed money damages for harm caused by biopharming.
To successful assert it, the plaintiff must demonstrate that biopharming is an “abnormally dangerous” activity. According to the Restatement of Torts §520, courts consider various factors to decide whether something is “abnormally dangerous”: (a) the existence of a high degree of risk of some harm to the person, land, or chattels of others, (b) the likelihood that the harm that results from it will be great; (c) the inability to eliminate the risk by the exercise of reasonable care, (d) the extent to which the activity is not a matter of common usage, (e) the inappropriateness of the activity to the place where it is carried on, and (f) the extent to which its value to the community is outweighed by its dangerous attributes.[157]
An illustration of the application of this multi-factor analysis to agriculture cases is Langan v. Helicopters .[158] First, the Langan court considered factor (a) met because a high degree of risk of harm existed due to the uncontrollability of pesticide drift. This uncontrollability stemmed from three “uncertain” factors: (1) the size of the dust or spray particles, (2) the air disturbances created by the application aircraft, and (3) natural atmospheric forces. Moreover, it noted the impossibility of eliminating this risk “with present knowledge and equipment.” Even the use of helicopters could only reduce but not eliminate the risk.[159] Second, the gravity of harm required by factor (b) was present because drifting pesticides were damaging to organic farmers like the two plaintiffs, in terms of both decreased marketability of crops and lost organic certification. Third, factor (c) was met for the same reasons discussed under factor (a). Fourth, the court considered factor (d) satisfied because even though crop dusting was “ordinarily done in large portions of the Yakima Valley,” the fact that it was carried out by “only a comparatively small number of persons” made it not a matter of common usage. Fifth, factor (e) was met because the land next to an organic farm was an inappropriate place for crop dusting. And finally, as for factor (f), the court acknowledged the social utility of pesticides in the control of insects, weeds, and other pests, but decided that an “equitable balancing of social interests” required the defendant to pay for the damage he caused. In doing so, the court emphasized that the plaintiffs were innocent victims who were eliminated from the organic food market; they should not have been made to suffer while the defendant profited from the crop spraying.
If applied to biopharming, a somewhat similar analysis might result.[160] First, biopharming poses the high degree of risk of harm required by factor (a) because pollen drift has at least the same degree of uncontrollability as pesticide drift. Furthermore, as suggested by the 2004 NRC report, the risk of gene flow is just as impossible to eliminate as that of pesticide drift. Second, as for factor (b), biopharm contamination causes even greater damage than pesticide contamination, since the latter just eliminates organic crops from the organic market (i.e., they can still be sold in the conventional crop market), whereas the former eliminates both organic and conventional crops from all markets. Third, factor (c) is met by the impossibility of eliminating risk discussed under factor (a). Fourth, under factor (d), biopharming is not a matter of common usage, nor will it be in the near future, as it is a very recent scientific development and only done on a small scale nationwide. Furthermore, even if biopharming is the dominant production method in a particular locality, as crop dusting was in the Yakima Valley where Langan arose, it still might not qualify as a matter of common usage because biopharmers represent a tiny minority of the total population of farmers.[161]
As for the fifth and six steps of the analysis however, factors (e) and (f) may be harder for a plaintiff to meet in a biopharming case. The “inappropriateness” required by factor (e) may be met if biopharming occurs in an area devoted to conventional farming. Indeed, the strongest case for “inappropriateness” would be growing biopharm corn in the heart of the Corn Belt, where the risk of contaminating the food supply is highest. But as for organic farming, the argument is trickier. Organic farmers could try to argue, as the court reasoned in Langan , that the plaintiff’s risky activity was especially inappropriate next to an organic farm. However, other courts might disagree with the Langan court’s analysis here, especially since Langan has captured “only lukewarm precedential interest” in other jurisdictions.[162] Instead, they might consider organic farming an “abnormally sensitive” activity. According to §524A of the Restatement, even if an abnormally dangerous activity causes harm, there is no strict liability if the harm would not have resulted “but for the abnormally sensitive character of the plaintiff’s activity.”[163] As noted earlier, the presence of biopharm material may not deprive organic farmers of certification under the process-based standards of USDA’s NOP. However, it may do so under the stricter standards of certain private, non-governmental organic organizations. These stricter standards may lend an “abnormally sensitive” character to organic farmers who adhere to them. Thus, plaintiff organic farmers may not wish to draw attention to the abnormally sensitive nature of their organic farming. Rather, they may tactically choose to just emphasize the inappropriateness of biopharming in land near farms that produce any food crops in general (both conventional and organic), due to the risk that biopharm “escape” poses to the food supply.[164]
And finally, in the sixth step of the analysis, it is unclear whether plaintiffs can convince courts that the social benefit of biopharming is outweighed by its dangerous attributes. Courts will weigh the benefit of large-scale, inexpensive production of life-saving pharmaceuticals and useful industrial compounds, against the risks posed to heath, environmental, and economic concerns. On the one hand, courts may adopt Langan’s reasoning and find strict liability because biopharm defendants should not be allowed to externalize their costs and profit at the expense of innocent victims, the plaintiffs. But on the other hand, courts may be hesitant to do so because biopharming has already received the federal government’s stamp of approval. If courts believe that biopharming is a valuable technology that can be carefully controlled by responsible stewardship, they may decline to find strict liability, and turn to the negligence standard instead.
Private nuisance is an actionable invasion of a possessor’s interest in the use and enjoyment of his land. If a plaintiff is unable to succeed on a trespass claim, he may still be able to assert a nuisance claim. Private nuisance usually involves something annoying, damaging, inconvenient, noxious, or offensive, such as noise, smoke, fume, odors, and barking dogs.[165] The elements of nuisance are: (1) “unreasonable” interference with the plaintiff’s use and enjoyment of his property, (2) caused by the defendant’s intentional or unintentional and otherwise actionable conduct.[166]
The first element turns on the word “unreasonable.” In some jurisdictions, private nuisance focuses primarily on the plaintiff’s interest invaded, not on the defendant’s culpability as negligence does. Courts consider ad hoc factors such as the original character of the neighborhood, priority of land ownership, frequency of intrusion, proximity to the plaintiff’s land, and effect of intrusions on the plaintiff’s use of his land.[167] Thus, the plaintiff will have a strong case if the neighborhood was originally devoted solely to conventional or organic farming (often the case because biopharming is not yet widespread), if he already owned his property before the biopharmer acquired his, if biopharm pollen or seed drifts over frequently, and if the defendant’s property is nearby. Furthermore, the plaintiff must demonstrate that the effect of the intruding pollen or seed was to interfere with the use and enjoyment of his land. He can easily do so by showing that he was forced to change the use of his land due to contamination (i.e., stop growing certain crops temporarily, or cease farming altogether). Furthermore, as stated in Lunda v. Matthews , zoning is not an approval of nuisance-causing conduct, and conformance to standards does not necessarily preclude a private nuisance suit. Thus, as applied to biopharming, the defendant might be held liable even if his land is zoned for biopharming, even if he has obtained a permit from APHIS, and even if he conforms to established stewardship practices.
Other jurisdictions, however, determine “reasonableness” by using a balancing test that weights the gravity of the harm against the utility of the defendant’s conduct.[168] In these jurisdictions, a conventional or organic farmer can use arguments like those above to prove interference with the use and enjoyment of his land. However, the plaintiff would still have to prove “unreasonableness” by showing that the gravity of the harm outweighs the social utility of biopharming. To determine the gravity of the harm, the court would likely act in accordance with the Restatement of Torts §827 and consider the following factors: (a) the extent of the harm to the plaintiff’s land, (b) the character of the harm, (c) the social value of his conventional or organic crops, (d) the suitability of his crops for that particular locality, and (e) the burden on him of avoiding biopharm contamination.[169] And to evaluate the social utility of biopharming, the court would follow §828 of the Restatement by considering the following factors: (a) the social value of biopharming (i.e., the inexpensive, large-scale production of valuable PMPs and PMIs), (b) the suitability of biopharming to the character of the locality, and (c) the impracticability of preventing or avoiding the invasion.[170]
Even if the court does find “unreasonable” interference, the second element of causation must also be met. Here, the same difficulties of proof discussed under trespass will arise. Fortunately for the plaintiff, even if he cannot determine the exact proportion of contamination from each of multiple biopharmers nearby (i.e., if they all grow the same variety), the court may still grant a remedy. That is because the court may consider itself “at liberty to estimate as best it could, from the evidence before it, how much of the total damage” was caused by each defendant. As persuasive authority, the court may look to California Orange Co. v. Riverside Portland Cement Co. , where two different cement plants were each held liable for the proportion of damage their dust was estimated to have caused to a neighboring orange grove.[171]
Next, even if the court concludes that the two elements of private nuisance are met, there remains the question of the remedy. If granting an injunction would create a “large disparity in economic consequences of the nuisance and of the injunction,” then the court may decide to grant permanent damages only.[172] For instance, in Boomer v. Atlantic Cement, Co. , the court denied the plaintiff’s requested injunction because the defendant had spent $40 million to construct the cement plant and the plant had over 300 employees.[173] Thus, as applied to biopharming, the court may consider the defendant’s investment in the production of biopharm crops and the impact on the agriculture and biotech industries. The defendant’s investment may be insubstantial if he is simply an individual farmer who has contracted to grow biopharm crops for a biopharm company. But if the defendant is a biopharm company that has invested millions in research and development, and also has many employees (i.e., not only in the fields, but also in experimental laboratories and purification facilities), the court may find the plaintiff’s individual losses insignificant in comparison and grant only damages. But of course, there is also the possibility that the court may consider the broader risk posed by biopharming on the safety of food supply. If so, it may conclude that no disparity exists and grant an injunction.[174]
Plaintiffs may also be able to claim public nuisance along with private nuisance. Public nuisance is a broad tort theory dealing with an “unreasonable interference with a right common to the general public.” Whereas private nuisance affects “a single individual or a definite number of persons” in the enjoyment of “some private right which is not common to the public,” public nuisance protects the common rights of all members of a community.[175] These common rights can involve public health, welfare, or safety. Though usually enforced by state officials or public agencies, certain jurisdictions allow private individuals to bring public nuisance suits and thereby act as citizen attorneys general. Such plaintiffs must allege a special injury apart from that of the public interest affected.[176]
The advantage of public nuisance is that, unlike all legal theories discussed earlier, it is not limited by the economic loss doctrine. This doctrine originated in products liability law, at the interface between tort and contract law, but it has grown beyond its origins into a doctrine about which forms of economic loss are recoverable in tort, even in the absence of a contract.[177] There is considerable variation across jurisdictions in caselaw regarding this doctrine.[178] But in general, it bars recovery if purely economic harm occurred, unaccompanied by physical harm. Only if physical harm also occurred, will the court allow the tort claim to proceed to proof. In In re StarLink , for instance, the court held that the economic loss doctrine did not bar the plaintiffs’ tort claims from proceed to trial. The court reasoned that, if contamination or commingling with StarLink corn was proven at trial, it resulted in physical property damage to the plaintiff farmers whose crops were no longer marketable as food. Thus, if applied to biopharming, the economic loss doctrine would permit recovery only for farmers whose crops had actually been contaminated by biopharm material. Conversely, it would bar recovery for farmers whose crops were not physically affected but who suffered nonetheless from the general risk of contamination, either because overall market prices fell, export markets closed, or because they had to bear additional market-imposed costs (i.e., testing procedures).[179] These lost profits are merely “disappointed commercial expectations” and will remain uncompensated.[180]
However, since public nuisance is not limited by the economic loss doctrine, it is not restricted to plaintiffs who suffered physical property damage. Potential plaintiffs include farmers whose crops were not physically affected but whose economic interests were harmed nonetheless, as well as non-farmers such as export traders and food processors. Thus, public nuisance may prove to be the most wide-sweeping liability claim against biopharm companies and growers. Indeed, the court in In re StarLink recognized the possibility that economic loss (e.g., corn price declines, export market losses) could be a compensable injury, even if the farmers never experienced direct contamination or commingling.[181] Though this case was ultimately settled, the fact that the public nuisance claim survived the initial motion to dismiss may serve as a precedent for future biopharm contamination lawsuits. Thus, public nuisance could potentially provide relief to numerous food industry participants who suffer export market losses, due to zero or less-than-zero tolerances adopted abroad.
To determine whether there is a public nuisance, the court will consider whether the interference with the common public right was “unreasonable.” According to §821B of the Restatement of Torts, circumstances that may render an interference “unreasonable” include the following: (a) whether the conduct involves a significant interference with the public health, safety, peace, comfort, or convenience, (b) whether the conduct is proscribed by a statute, ordinance, or administrative regulation, or (c) whether the conduct is of a continuing nature or has produced a permanent or long lasting effect, and, as the actor knows or has reason to know, has a significant effect upon the public right.[182]
As Comment f to this section explains, even if certain conduct would be a public nuisance at common law, the fact that it is “fully authorized by statute, ordinance, or administrative regulation does not subject the actor to tort liability.”[183] Hence, courts cannot declare all biopharming a public nuisance per se because federal regulation authorizes biopharming via APHIS permits. They can only declare individual instances of biopharm contamination resulting from regulatory non-compliance to be public nuisances.
And indeed, even when courts find a public nuisance, they may struggle over the issue of what remedy to select. As Comment I to §821 explains, if a general activity has “great utility,” it may be reasonable to decline to grant an injunction but still require the plaintiff to pay for the harm done.[184] Courts might decline to issue injunctions if they believe biopharming offers “great utility” and do not want this new technology to be unduly stifled. Furthermore, courts may be especially hesitant to routinely issue injunctions in all cases of biopharm contamination (potential or continuing), because this would virtually overrule the U.S. federal government’s regulatory approval of biopharm crops. Particularly if the injunction request was motivated by a desire to protect export markets, granting the injunction would essentially amount to allowing foreign governments’ stricter regulatory standards (i.e., zero-tolerance or less-than-zero tolerance) to override U.S. federal regulatory standards for agricultural biotechnology.[185] Hence, courts may find “great utility” in most cases, and only grant injunctions in egregious cases, such as when contamination results from extreme carelessness.
But of course, as Comment I states, courts that decline to grant injunctions may still award monetary damages if it would be unreasonable to allow the identified harm without compensating for it. Essentially, courts will decide whether there should be a “socialization of harm” or an internalization of costs. That is, they must decide whether society as whole should bear the burden of the socially useful activity of biopharming, or whether plaintiff biopharmers should compensate innocent victims for the harm done.[186]
And finally, on a related note, perhaps the mere threat of an injunction to prevent a public nuisance may be sufficient. For instance, the threat of injunctive relief was used successfully to restrain the sale of Aventis’ “Liberty Link” GM soybeans, an unapproved-in-EU variety. Fearing for export markets, the American Soybean Association (ASA) wanted to prevent conventional and organic soybeans from being commingled with unapproved-in-EU varieties of GM soybeans. It thus asked eleven biotech companies, including Aventis, to refrain from marketing new varieties of GM soybeans that lacked approval abroad. When Aventis at first ignored this request, ASA spent several months “educating” the company about potential public nuisance liability for commingling. Faced essentially with the threat of injunctive relief, Aventis ultimately backed down and did not market Liberty Link. One can imagine a similar scenario in the future, where the threat of an injunction could compel biopharmers to behave responsibly.
Overall, the legal liability system may provide both compensation and deterrence. Ex
post, it compensates those harmed by biopharm “escape,” thus forcing biopharmers to internalize previously externalized costs. Ex ante, the risk of multi-million dollar liability or injunctive relief may also deter biopharmers from engaging in careless, inadequate stewardship.
However, though the legal liability system may be a useful supplement to the federal regulatory regime, it is quite an expensive option. Furthermore, though litigation may provide some ex ante deterrence, it all too often only arises ex post, after severe or irreparable harm has already been done. If harm is severe, imposing heavy damages could compensate injured plaintiffs, but might simultaneously force biopharmers to shut down or stifle investment in this promising new technology.[187] And if harm is irreparable, no amount of damages may fully compensate injured victims. Thus, given these shortcomings of the legal liability system, we should also consider alternative policy proposals to minimize the risks of biopharming and prevent disasters ex ante.
At one extreme of the spectrum is the proposal to ban biopharming completely.
However, this view is espoused mainly by activist environmental groups and is unlikely to be accepted by the mainstream, especially since the U.S. federal regulatory regime has already given biopharming its official stamp of approval. Other, more moderate proposals aim to modify the current method of biopharming—open-field production using food crops.
Given the high risk of “escape” associated with open-field biopharming, consider the alternative of contained production methods like rhizosecretion and plant cell cultures. Both methods offer the advantages of total containment, complete control of growth conditions, ease of extraction, and continuous harvest.
Take, for instance, rhizosecretion. It involves the secretion of biopharm proteins from plant roots into hydroponic media. A promising example is a small aquatic plant called lemna. Lemna offers low risk of escape not only because it can be totally contained with greenhouses, but also because it does not require seeds or pollen for reproduction. Since new lemna plants simply sprout off old ones, there is no risk of seeds or pollen escaping the greenhouse via contaminated employee clothing or equipment. Additionally, growth in greenhouses allows for complete control of production conditions, which in turn improves consistency of drug quality. Furthermore, engineered lemna plants simply secret pharmaceutical proteins into the water they grow in. This simplifies harvesting because extracting and purifying proteins from water is easier than doing so from whole-plant tissue. Recognizing these numerous advantages, companies such as Biolex of North Carolina have already been using lemna. According to Biolex CEO David Spencer, the major advantages of this plant are “speed, economics, and regulatory compliance.”[188]
However, it is important to keep in mind that contained production systems like rhizosecretion and plant cell cultures would have to take place within greenhouses or laboratories. Since such buildings are expensive to build and operate, some of the original benefits of biopharming would be lost (i.e., production capacity, production flexibility, and associated cost savings).
As mentioned earlier, the “escape” of biopharm material into the food supply is both highly likely and potentially disastrous. Thus, perhaps the best solution is simply to limit biopharming strictly to non-food host plants. This is essentially the recommendation of the January 2004 NRC scientific report. Specifically, the report stated that a plant used for food would be a “poor choice” for biopharming unless it is raised under extremely “stringent conditions of confinement.”[189]
Corn is by far the most popular food crop currently used for biopharming. More than two-thirds of all open-air field trials have involved corn.[190] The advantages of corn are that it is easy to engineer, produces large amounts of protein, and can be stored for months or years without the proteins breaking down. Other plants do not offer the same ease of storage; tobacco, for example, must be frozen.[191] However, corn is also extremely prone to cross-pollination. It routinely breeds with related crop varieties and spontaneously mates with wild relatives.[192] Furthermore, large amount of pollen and seed can spread for long distances via birds, insects, and especially the wind. This makes it quite difficult to prevent contamination of regular corn crops by biopharm corn.[193] Given that corn is such an integral part of America’s food supply, using corn for biopharming could unleash a host of grave problems. Another StarLink-type disaster could very well occur again, with potentially worse consequences if it involves PMPs or PMIs that are unsuitable or even unsafe for human consumption.
Increasingly, biopharming companies are recognizing the extreme difficulty of keeping pharmaceutical corn out of the food supply, especially the portion originating from the Corn Belt. Memories of the StarLink debacle also linger on everyone’s minds. As a sign of the industry’s anxiety, BIO even announced on October 24, 2002 a voluntary moratorium on biopharm corn crops in the Corn Belt for the upcoming planting season in 2003, although this proposal was soon thereafter abandoned.[194] In search for viable long-term alternatives, some companies have begun to consider other regions of the country, as well as other types of host plants altogether.[195]
The possibilities seem to abound, but not without drawbacks. Safflower, for instance, though occasionally used for vegetable oil, is not grown widely in North America. This decreased likelihood of cross-pollination makes it an attractive target for biopharming. Indeed, the Canadian company SemBioSys has already engineered safflower to make therapeutic proteins, and is experimenting with such production in Iowa. There is at least one potential hurdle, however; certain states’ climates may be too humid for safflower.[196]
Rubber trees are another possibility. According to the American Association for the Advancement of Science, researchers at the Rubber Research Institute of Malaysia have succeeded in transforming rubber trees to express a beta-glucuronidase (GUS) reporter gene in the milky latex sap. In terms of productivity, a mature, 5-year old tree can produce 100-200 milliliters of sap every two days for 30 years. However, such long-term productivity is secured at the cost of refraining from tapping the sap of seedlings for the first two and a half years, thereby allowing trees to become established and grow vigorously. These initial two years of non-productivity may be a significant economic drawback for companies seeking to recoup investments quickly. Furthermore, researchers must still determine whether the expression of other inserted genes will also be concentrated in the sap, how much foreign protein is extractable from the sap, and whether proteins will retain their pharmaceutical activity.[197]
Tobacco might be the most promising alternative. First of all, its relative tractability to genetic engineering makes it an attractive choice for biopharming. In fact, it is widely used as a model system to test the feasibility of plant-based expression systems for the production of transgenic proteins and other pharmaceuticals. Scientists have engineered more transgenes into the tobacco chloroplast or nuclear genome than all other crops combined.[198] For instance, a California company called Large Scale Biology is reportedly creating personalized cancer vaccines in tobacco for the treatment of non-Hodgkin’s lymphoma.[199] Secondly, tobacco offers the advantage of high productivity. It produces significant biomass, more than 40 tons of leaf fresh weight per acre (based on multiple cuttings per season). Each tobacco plant can produce up to a million seeds, so this high productivity minimizes the time in which a product can be scaled up in production and brought to the market.
Even more importantly, tobacco may be more easily contained than other crops. First, it is not used for food or animal feed, and is not usually grazed upon by wildlife. Second, there is minimal risk of tobacco seed being produced or for seed to be carried over and sprouting “voluntarily” in subsequent seasons. This is because tobacco plants must be grown in seedbeds for two or three months before transplantation into the field, and their flowers are usually removed even before they open. Third, large buffer zones are not necessary since it is unlikely for cross-pollination with nearby tobacco fields to occur when the flowers are either removed or covered with bags.[200] Fourth, advanced techniques for male sterility and seed sterility have already been developed for the plant. And finally, tobacco has no known wild or cultivated relatives in North America. This should dramatically reduce the likelihood of gene flow.[201] In fact, some USDA officials have specifically recommended tobacco as a good alternative to food crops like corn.[202]
Of course, tobacco is not without its shortcomings. First, as mentioned earlier, tobacco must be frozen, and hence does not offer the same ease of storage as corn. Second, many companies have already invested tremendous money in food crop biopharming technology, and thus are hesitant to switch over to tobacco because it would require the development of new extraction techniques to get rid of toxic alkaloids (e.g., nicotine).[203] And third, vegetative tissue rather than seed would have to be used for PMP or PMI expression because seed makes up only a small percentage weight of tobacco plants. But commercial-scale extraction of proteins from vegetative tissue containing a high proportion of water could result in proteolysis (i.e., the hydrolytic breakdown of proteins into simpler, soluble substances such as peptides and amino acids, as occurs during digestion). This lowers the efficiency and increases costs, possibly making tobacco only economically feasible for PMPs that can fetch high market prices.[204]
While the above alternatives eliminate some risks associated with the current method of biopharming, they also sacrifice some of its key benefits. Thus, they are unlikely to be embraced widely by most biopharmers, especially since the U.S. regulatory framework is already designed with the current method in mind. At most, these alternative methods will supplement but not displace the current method of open-air biopharming using food crops. Given this reality, we must explore other proposals to minimize the risks attendant with this current method. Ideally, the following proposals may form part of a comprehensive solution to the risks posed by biopharming.
As mentioned earlier, federal regulators have declined to adopt non-zero tolerances for biopharm material in food, resulting in an effectively zero tolerance standard. To more explicitly enforce this zero tolerance standard, the Bush administration in June 2003 proposed an FDA rule stating that PMPs and PMIs are “unapproved food additives” subject to the adulteration provisions of the 1938 Federal Food, Drug and Cosmetic Act. [205] Under this proposal, the detection of traces of biopharm material would result in the immediate seizure of tainted food products from grocery stores shelves.[206] This proposal rule is being considered by an interagency agriculture biotechnology task force, created by the White House National Economic Council and Office of Science and Technology Policy.[207]
However, as shown earlier, it seems extremely difficult, if not impossible, to completely prevent biopharm contamination of the food crops. It has already occurred (i.e., ProdiGene), and could very well happen again. Hence, the zero tolerance standard creates enormous risk for the U.S. food industry, making it vulnerable to massive recalls and brand erosion.
A possible alternative is for federal regulators to adopt a post-market non-zero tolerance standard based on individualized risk assessment. On the one hand, federal regulators would continue to stress the importance of containment measures. But on the other hand, the FDA could acknowledge the virtual inevitability of biopharm contamination and establish non-zero tolerance standards for PMPs and PMIs that inadvertently enter the food supply. Such standards could vary according to individualized risk assessments of each individual PMP or PMI. In other words, the FDA would determine the threshold level at which each biopharm substance becomes unsafe for human consumption, and then establish a non-zero tolerance at or below that level.
Indeed, the idea of non-zero tolerance has always existed in the food industry. For instance, grain products are never completely free from contamination by adulterants such as poisonous fungi, rodent hair and droppings, and insect parts. Just like PMPs and PMIs, these adulterants are “not intended for food and feed use,” but are nevertheless tolerated at low, non-zero levels. Jut as grain producers and the FDA have cooperated to design risk assessment and management approaches for such adulterants, they should be able to do the same for PMPs and PMIs.
A stricter alternative is to establish post-market non-zero tolerance only for those PMPs and PMIs that do not pose a danger to humans when consumed in any quantity (i.e., at all concentration levels). Specifically, there is the possibility that at least certain PMPs and PMIs could qualify for “generally recognized as safe” (GRAS) status under FDA regulations.[208] According to Eric Famm, a senior policy advisor to the FDA Commissioner, as long as companies can demonstrate to the FDA that scientists think that a particular PMP is safe to eat, it may qualify under the existing standards of the GRAS process.[209]
An even stricter alternative would be to impose both a post-market and a pre -market ban on the subset of PMPs and PMIs that are dangerous for human consumption, in any quantity. This would be simultaneously accompanied by a non-zero tolerance standard for all the remaining PMPs and PMIs (i.e., those that are safe in any quantity) that fall outside of this dangerous subset.
In contrast to the aforementioned alternatives, this alternative would impose a complete ban on the subgroup of dangerous PMPs and PMIs. Not only would food supply contamination by such PMPs and PMIs result in automatic recalls under the zero tolerance standard, but APHIS would also prohibit (i.e., refuse to issue field test permits) biopharm companies from even growing them in the first place. This alternative would ensure greater safety than the above two proposals. If the only biopharm plants allowed to be grown are those that do not pose a danger to humans when accidentally consumed, the food supply’s safety will not be threatened even if biopharm contamination occurs.[210]
There are signs that federal regulators are considering a shift to some version of the non-zero tolerance standards described in the proposals above. For instance, APHIS is considering the possibility of replacing the current permit system with a “multi-tiered, risk-based permitting system,” which commentators say could amount to a relaxation of the current de facto zero tolerance standard for biopharm material in the food supply.
However, note that a non-zero tolerance standard would only resolve domestic food supply problems (i.e., the risk of recalls). Overseas regulatory authorities would probably still withhold approval for, and thus bar exports of, biopharm crops and any food that has traces of biopharm material. As mentioned earlier, the EU, Japan, and other countries will most likely extend their zero-tolerance model for GM food crops to biopharm crops. Thus, even if the U.S. adopted a non-zero tolerance standard, other measures would still be necessary to preserve U.S. international trade in export markets.
A single major disaster due to the careless stewardship of one irresponsible biopharm company could threaten the entire biopharm industry, in terms of credibility, image, investor confidence, capital attraction, and regulatory backlash. Thus, all industry participants have an interest in self-regulation, or “mutual policing,” to prevent biopharm “escape.”[211] This self-regulation could take the form of creating industry-wide “standard operating procedures” (SOPs) and then implementing them via contract on the entire chain of commerce.
SOPs could be developed with input from all interested parties. Such SOPs could include specific risk mitigation measures for each stage of biopharming—field testing, clinical trials, commercial field production, laboratory extraction/purification, waste disposal—as well as transportation between each stage (i.e., from fields to laboratories to the market). For instance, to prevent excessive on-site worker exposure to biopharm material, possible SOPs include: (1) personal protective equipment like masks and full -body suits, and (2) barriers around the chemicals and processing equipment.[212] And to prevent other forms of biopharm escape, SOPs could go beyond the basic containment measures mandated by APHIS regulations (e.g., buffer zones), to require a comprehensive stewardship system that would isolate biopharm material with multiple degrees of separation. That is, SOPs could require a system with built-in redundancy via the use of all possible containment measures—physical (detasseling, tassel bagging, dedicated machinery), spatial (buffer zones, “grower regions”), temporal (atypical growing seasons), and bioconfinement (male sterility, terminator genes, suicide genes) measures.[213]
Once created, such SOPs could be imposed on the entire chain of participants via contract. Accordingly, a responsible party at each and every stage would have to certify in writing that all procedures have been carried out in compliance with SOPs.
Furthermore, this documented certification at every stage of commerce could in turn be used to create an identity preservation system. Specifically, an identity preservation system would take the form of a closed-loop, “chain-of-custody” system. It could be modeled on existing systems for certified seed and organic crops, and then tailored by incorporating SOPs that address the unique risks of biopharming.
Given the many risks posed by biopharming, an identification preservation system could be a crucial part of the solution. As the USDA explicitly acknowledged in a Federal Register notice, “the emergence of value-enhanced commodities and a niche market for non-biotechnology-derived commodities” has created a “greater need to differentiate products in the handling system.”[214] Originally, after the first wave of agricultural biotechnology, divergent consumer preferences created the need to differentiate GM food crops from two categories—non-GM crops and organic crops. Now with biopharming, the second wave, there is the additional need to differentiate biopharm crops from those three categories—GM food crops, non-GM crops, and organic crops.
An identity preservation system would offer several significant benefits. First, it would ensure the quality, purity, and consistency of the final product (PMPs and PMIs). Second, it would strengthen compliance with confinement measures designed to protect human health and the environment from inadvertent exposure to biopharm material. And third, perhaps most importantly, it would boost consumer confidence in labels and thus help preserve the integrity of non-GM and organic markets, both domestic and international. Hence, identification preservation would greatly reduce the social and economic burdens currently borne by affected third parties (i.e., conventional farmers, organic farmers, commodity traders, food processors, and U.S. food exporters).[215]
However, note that an identity preservation system could actually be moot if foreign countries adopt a less-than-zero tolerance standard, especially in light of the Cartagena Protocol. Under this standard, even if an identity preservation system strives to fully isolate biopharm crops from food crops, the mere existence of biopharming in the U.S. may lead foreign countries to reject U.S. exports because they “may contain” traces of biopharm material. Indeed, foreign regulatory authorities may be required by law to assume that biopharm material may be present at some low percentage, and actual testing for genetic contamination may not even be required.[216]
Since none of the previous proposals, even that of an identity preservation system, can ensure the protection of U.S. export markets, the only viable solution may be to change international public attitudes in the long-run. Given their deep apprehension of GM foods, it is unlikely foreign authorities like the EU will accept anything but a zero or less-than-zero tolerance for biopharm material in U.S. food exports. Changing public attitudes may be the only means to “peaceful co-existence” between biopharming and the U.S. food trade.
One way to change public attitudes worldwide is to foster open dialogue between all
interested parties—biopharmers, conventional farmers, organic farmers, commodity traders, food processors, exporters, scientists, patient advocates, environmentalists, public interest groups, and the general public. One common complaint of the federal regulatory regime is a lack of transparency. For instance, out of concern for “eco-terrorism,” APHIS usually does not reveal the location of biopharm field test sites, the identity of the PMPs or PMIs being produced, or the amount of acreage under cultivation.[217] It recognizes that much of this information may be “confidential business information” (CBI) for biopharm companies, and thus condones these companies’ preferred practice of “anonymously” planting the biopharm crops without identification or notification of neighbors.[218] However, the resulting “veil of secrecy” not only angers environmentalists and affected third parties, but also reinforces public distrust of biopharming in general.
Of course, biopharm companies have a right, or even a fiduciary duty, to refrain from disclosing CBI. But to the extent possible, disclosure should be encouraged in order to foster open dialogue with all interested parties about the benefits and risks of biopharming. Such open dialogue could prove quite beneficial. For instance, it could facilitate an independent evaluation of potential health and environmental hazards posed by biopharming. Such an independent evaluation would have more credibility with the public than APHIS, which the public may distrust because it serves the dual role of regulating and promoting biopharming. If the independent evaluation concluded that biopharming risks are minimal or at least controllable, the international public’s fears might be alleviated to a certain degree.
APHIS has already taken steps in this direction. Perhaps in response to recent complaints, APHIS claims it has made a concerted effort to increase transparency in its regulatory system. When APHIS announced several changes in 2003, for instance, it posted announcements on its websites and the Federal Register. It also briefed the biotech, food, and agricultural industries, NGOs, academic researchers, Capitol Hill, and the media. In general, it has been reaching out to a wider range of groups. It has even partnered with certain groups, such as the National Association of State Directors of Agriculture, in the regulation of field trials. [219] In the future, further efforts should be made in this direction, on both a domestic and international level, so that public attitudes can become more receptive to the idea of biopharming.
Perhaps an even more effective way to persuade foreign countries to accept the new technology of biopharming is to convince them of the great potential benefits they can reap directly. For instance, an active initiative has been undertaken to promote vitamin A-enriched “golden rice” abroad; this GE food crop can prevent blindness in thousands of people plagued by malnutrition. A similar approach should be taken with biopharm crops. If U.S. companies share with foreign countries the benefits of biopharming—such as inexpensive, high yields of life-saving PMPs and valuable PMIs, as well as high premiums for individual farmers contracted to produce these products—this may significantly increase consumer acceptance of biopharming abroad.[220]
Biopharming is a revolutionary technology that offers the dramatic benefits of cost-efficient, high yields of life-saving pharmaceuticals and useful industrial compounds. However, the escape of biopharm material is virtually inevitable and potentially devastating to the environment, human health, and economic interests. The current U.S. federal regulatory system strives to control the dangers of biopharming, but its relative focus on pre-market approval leaves a gap in post-market oversight. This gap can be partially filled by the legal liability system, which can provide an additional layer of post-market oversight by mobilizing affected third parties as private attorneys general. However, due to the high cost of litigation and the inadequacy of the legal system to prevent problems ex ante, additional policy measures may be necessary. A partial solution may lie in regulatory changes and self-regulation designed to better minimize the risks of biopharming. But these offer only a domestic solution, and in the long run, crucial U.S. export markets can only be preserved if efforts are made to alleviate the international community’s deeply rooted fears about biopharming. Once this comprehensive regime of measures is in place, it is likely that the U.S. and indeed the entire world will be able to safely reap the extraordinary benefits of biopharming.
[1] ‘Biopharming’: USDA Needs to Rewrite Its Rules , STAR-TRIBUNE , Jan. 27, 2004, at 12A [hereinafter Rewrite ].
[2] Geoffrey Lean, Genetically Modified Rice to be Grown for Medicine , ZEALAND HERALD , Feb. 2, 2004, at A12.
[3] “Biologics” provide the building blocks for drugs targeting cancer, heart disease, HIV, and other debilitating diseases.
[4] Allan S. Felsot, “Pharm Farming”: It’s Not Your Father’s Agriculture , AGRICHEMICAL AND ENVIRONMENTAL NEWS , available at http://www.aenews.wsu.edu/July02AENews/PharmFarming/PharmFarming.pdf (July 2002).
[5] Roundtable: Is There a Pharm in the Future? , AGBIOTECH BUZZ , at http://pewagbiotech.org/buzz/ display.php3?StoryID=68 (July 29, 2002) [hereinafter Roundtable ].
[6] Friends of the Earth, Manufacturing Drugs and Chemicals in Crops: Biopharming Poses New Risks to Consumers, Farmers, Food Companies and the Environmen t (Executive Summary), available at http://www.foe.org/camps/comm/safefood/biopharm/biopharmexec.pdf (July 2002), at 6 [hereinafter Manufacturing Drugs (Executive Summary) ].
[7] USDA’s Biotech Chief Foresees Bigger, Stronger Agency , FOOD CHEMICAL NEWS , Sept. 1, 2003, at 11 [hereinafter Biotech Chief ].
[8] ProdiGene’s Website, http://www.prodigene.com (last accessed April 21, 2004).
[9] Pat Walsh, Keep Biopharming in Greenhouses , DENVER POST , June 7, 2003, at B23.
[10] Lean, supra note 2.
[11] See Philip Brasher, ‘Pharmacorn’ Could Face Competition , DES MOINES REG ., June 29, 2003, at A1 [hereinafter Pharmacorn ]; see also Lean, supra note 2.
[12] Henry Miller & David Longtin, Down on the Biopharm , POLICY REVIEW, Dec. 1, 2003, at 55.
[13] Walsh, supra note 9.
[14] Manufacturing Drugs (Executive Summary) , supra note 6, at 7.
[15] Glynis Giddings et al. , Transgenic Plants as Factories for Biopharmaceuticals , 18 NATURE BIOTECHNOLOGY 1151, 1151 (2000), available at http://hmb.utoronto.ca/HMB301H/2004/HMB301hlec4and5/trans%20plants %20factories.pdf .
[16] Transcript of the “Plant-Derived Biologics Meeting,” available at http://www.fda.gov/cber/minutes/ plnt1040500.pdf (Apr. 2000).
[17] Tsafrir S. Mor et al., Perspective: Edible Vaccine–A Concept Coming of Age , 6 TRENDS IN MICROBIOLOGY 449 (1998).
[18] P. Helena Mäkelä, Vaccines, Coming of Age After 200 Years , 24 FEMS MICROBIOLOGY REVIEWS 9 (2000), available at http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T37-3YB4DCJ-2&_coverDate=01% 2F31%2F2000&_alid=157308444&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=4939&_sort=d&view=c&_acct=C000014438&_version=1&_urlVersion=0&_userid=209690&md5=a86e7dfedec1f0e7875fe434a9605909
[19] Manufacturing Drugs (Executive Summary) , supra note 6, at 9-10.
[20] Walsh, supra note 9.
[21] Pharmacorn , supra note 11.
[22] Id.
[23] Forum , Information Systems for Biotechnology, at http://www.isb.vt.edu/articles/MAR9011.htm (Mar. 1990).
[24] Forum , supra note 23.
[25] Roundtable , supra note 5.
[26] Lon Crosby, Commercial Production of Transgenic Crops Genetically Engineered to Produce Pharmaceuticals , BIOPHARM INTERNATIONAL , available at http://www.biopharm-mag.com/biopharm/data/articlestandard/biopharm/ 172003/54511/article.pdf (Apr. 2003).
[27] Roundtable , supra note 5.
[28] Pharming the Field: A Look at the Benefits and Risks of Bioengineering Plants to Produce Pharmaceuticals (Conference Report ), Pew Initiative on Food and Biotechnology, at http://pewagbiotech.org/events/0717/ ConferenceReport.pdf (Feb. 2003), at 2 [hereinafter Pharming the Field ].
[29] Miller & Longtin, supra note 12.
[30] Id.
[31] Mammalian and fungi cultures are common. For example, a wide range of therapeutic proteins (i.e., immunoglobulins) are currently produced in cultures of Chinese hamster ovary cells, which divide rapidly and can easily be transformed to replicate and transcribe DNA from humans and other organisms.32 See Felsot, supra note 4.
[33] These complexes are energy-intensive due to strict temperature control.
[34] See Miller & Longtin, supra note 12.
[35] Aaron Zitner, Fields of Gene Factories , L.A. TIMES , June 4, 2001, at A-1.
[36] Henry Daniell, Production of Human Serum Albumin in Transgenic Crops Without Interfering with Food or Feed Production , at http://www.isb.vt.edu/articles/sep0304.htm (Sept. 2003).
[37] Miller & Longtin, supra note 12.
[38] Giddings et al., supra note 15, at 1151.
[39] Daniell, supra note 35.
[40] Zitner, supra note 34.
[41] Zitner, supra note 34.
[42] Pharmacorn , supra note 11.
[43] Crosby, supra note 26.
[44] Giddings et al., supra note 15,
[45] Friends of the Earth, Manufacturing Drugs and Chemicals in Crops: Biopharming Poses New Risks to Consumers, Farmers, Food Companies and the Environment (Updated Factsheet), available at www.foe.org/biopharm/bioqanda.pdf (Feb. 2004), at 3 [hereinafter Manufacturing Drugs (Updated Factsheet) ].
[46] Friends of the Earth, Manufacturing Drugs and Chemicals in Crops: Biopharming Poses New Risks to Consumers, Farmers, Food Companies and the Environmen t, available at www.foe.org/biopharm (July 2002), at 97 [hereinafter Manufacturing Drugs ].
[47] Philip Brasher, Scientific Panel Issues Warning About Biotech Crops , DES MOINES REG. , Jan. 21, 2004 [hereinafter Scientific Panel ].
[48] Thomas P. Redick, Biopharming, Biosafety, and Billion Dollar Debacles: Preventing Liability for Biotech Crops, 8 DRAKE J. AGRIC. L. 115, 128 (2003).
[49] Zitner, supra note 34.
[50] See Alex Binkley, Canada Report Assess Fallout from StarLink Corn Controversy , FOOD CHEMICAL NEWS , Dec. 24, 2001, at 9; see also Randy Fabi, Exporters Say Japan Finds StarLink in U.S. Corn Cargo , TORONTO STAR , Dec. 30, 2002, at D5.
[51] Rewrite , supra note 1.
[52] Michael R. Taylor & Jody S. Tick, Post-Market Oversight of Biotech Foods: Is the System Prepared? (Executive Summary) , Pew Initiative on Food and Biotechnology, at http://pewagbiotech.org/research/postmarket/ PostMarketExecSum.pdf (Apr. 2003).
[53] Rewrite , supra note 1.
[54] Miller & Longtin, supra note 12.
[55] Press Release, Grocery Manufacturers of America, GMA Urges the Use of Non-Food Crops for Biotech Drugs: ProdiGene's Errors Raise Serious Concerns, Says GMA (Nov. 14, 2002), available at http://www.gmabrands.com/ news/docs/NewsRelease.cfm?DocID=1029 (on file with author) [hereinafter GMA Urges the Use of Non-Food Crops ].
[56] Walsh, supra note 9.
[57] Rewrite , supra note 1.
[58] James Cole, Scientific Approach to Science Learning , WORLD TOBACCO , July 1, 2003, at 40.
[59] Biotech Chief , supra note 7.
[60] PEW Initiative on Food and Biotechnology, Gene Flow Common, But Genetically Modified (GM) Crops Raise New Concerns About Age-Old Phenomena , at http://pewagbiotech.org/newsroom/releases/081803.php3 (Aug. 18, 2003) [hereinafter Gene Flow Common ].
[61] See Scientific Panel , supra note 46; see also Pharming the Field , supra note 28, at 33.
[62] Gene Flow Common , supra note 59.
[63] Id.
[64] Forum , supra note 23.
[65] Roundtable , supra note 5.
[66] Forum , supra note 23.
[67] Felsot, supra note 4.
[68] Felsot, supra note 4.
[69] Manufacturing Drugs (Updated Factsheet) , supra note 44, at 2.
[70] Roundtable , supra note 5.
[71] Giddings et al., supra note 15, at 1154.
[72] Manufacturing Drugs (Updated Factsheet) , supra note 44, at 2.
[73] Emerson Nafziger, Corn Moving Through Grainfill , PEST MANAGEMENT & CROP DEVELOPMENT BULLETIN , available at http://www.ag.uiuc.edu/cespubs/pest/articles/v9722i.html (Aug. 29, 1997).
[74] Terrence Fay & Nicholas Phillips, Safe Handling of Potent Compounds , CHEMICAL ENGINEERING, April 1,
2002, at 62.
[75] Walsh, supra note 9.
[76] Redick, supra note 47, at 119.
[77] Manufacturing Drugs , supra note 45, at 95.
[78] Manufacturing Drugs (Executive Summary) , supra note 6, at 7.
[79] Manufacturing Drugs (Executive Summary) , supra note 6, at 7.
[80] Giddings et al., supra note 15, at 1154.
[81] Roundtable , supra note 5.
[82] Manufacturing Drugs (Executive Summary) , supra note 6, at 7.
[83] Forum , supra note 23.
[84] Lean, supra note 2.
[85] The CDC published a report stating that there was no evidence that the allergic reactions of persons claiming injury were actually caused by the Cry9c protein. See Centers for Disease Control and Prevention, Investigation of Human Health Effects Associated with Potential Exposure to Genetically Modified Corn , available at http://www.cdc.gov/nceh/ehhe/Cry9cReport/executivesummary.htm (2001).
[86] Mike Robinson, Judge Approves $9 Million Settlement in Bioengineered-Corn Suit , ASSOCIATED PRESS , Mar. 8, 2002, available at http://www.enn.com/news/wire-stories/2002/03/03082002/ap_46626.asp .
[87] GMA Urges the Use of Non-Food Crops , supra note 54.
[88] According to the GMA, it is the world’s largest association of food, beverage, and consumer companies. Its member companies employ enjoy combined U.S. sales of more than $500 billion and employ over 2.5 million workers. The 10 other U.S. food industry trade associations were as follows: the American Bakers Association, the Biscuit & Cracker Manufacturers Association, the Food Marketing Institute, the Institute of Shortening & Edible Oils, the International Dairy Foods Association, the National Confectioners Association, the National Council of Chain Restaurants, the National Restaurant Association, the National Soft Drink Association, and the Snack Food Association. See U.S. Grocery-Makers’ Body Comments on Bio-Pharma Permit Regulations , NUTRACEUTICALS INTERNATIONAL , July 1, 2003 [hereinafter U.S. Grocery-Makers’ Body Comments ].
[89] Id.
[90] Guy Hatchard, U.S. Farmers Reap Heavy Penalty for Sowing GM Crop s, NEW ZEALAND HERALD , Aug. 27, 2002, available at http://www.nzherald.co.nz/storyprint.cfm?storyID=2351302 .
[91] Press Release, Pew Initiative on Food and Biotechnology, Trade War Over Biotech Food: Now, Later or Never? , available at http://pewagbiotech.org/newsroom/releases/021303.php3 (February 13, 2003) (on file with author) [hereinafter Trade War ].
[92] Felsot, supra note 4.
[93] Trade War , supra note 90.
[94] Hatchard, supra note 89.
[95] U.S. State Department, Bureau of Oceans and International Environmental and Scientific Affairs, Fact Sheet: Cartagena Protocol on Biosafety , available at http://www.fas.usda.gov/info/factsheets/biosafety.html (July 21, 2003).
[96] Redick, supra note 47, at 116 (2003).
[97] For an example of a less-than-zero tolerance standard, consider the experience if Australian exporters. New Zealand refused a shipment of Australian cottonseed without even testing it for GM contamination, because it knew that some GM cotton was being grown in Australia. See Redick, supra note 47, at 141.
[98] Hatchard, supra note 89.
[99] Jerry Perkins, Drop in Corn Exports Cuts Railroad Business , DES MOINES REG ., Nov. 17, 2001, at 1D.
[100] Committee on Environmental Impacts Associated with Commercialization of Transgenic Plants, Board on Agriculture and Natural Resources, Division of Earth and Life Sciences, National Research Council, Environmental Effects of Transgenic Plants: The Scope and Adequacy of Regulation , available at http://www.nap.edu/books/ 0309082633/html (2002), at 1 [hereinafter Environmental Effects of Transgenic Plants ].
[101] Biologics and human drugs are regulated by the FDA’s Center for Biologics Evaluation and Research (CBER) and Center for Drug Evaluation and Research (CDER) respectively, under the authority of the Public Health Service Act (PHS Act) (42 U.S.C. §262 et seq .) and the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. §301 et seq. ).
[102] Felsot, supra note 4.
[103] Biotech Chief , supra note 7.
[104] FDA, Draft Guidance for Industry: Drugs, Biologics, and Medical Devices Derived from Bioengineered Plants for Use in Humans and Animals , at http://www.fda.gov/cber/gdlns/bioplant.pdf (Sept. 2002) [hereinafter Draft Guidance for Industry ].
[105] Press Release, State Department, USDA Announces First Steps to Update Biotech Rules (Jan. 23, 2004) (on file with author) [hereinafter First Steps ].
[106] 7 U.S.C. §7701 et seq. (2004). The Plant Protection Act was passed in 2000. It is largely a consolidation of authorities found in preexisting statutes, including the Federal Plant Pest Act and the Plant Quarantine Act.
[107] Draft Guidance for Industry , supra note 103.
[108] 7 C.F.R. §340 (2004).
[109] First Steps , supra note 104.
[110] See Biotech Chief , supra note 7; see also U.S. Grocery-Makers’ Body Comments , supra note 87.
[111] Miller & Longtin, supra note 12.
[112] Miller & Longtin, supra note 12.
[113] BRS, What Additional Changes has BRS made to Date to Strengthen Compliance with its Regulations? , at http://www.aphis.usda.gov/brs/compliance2.html (last visited Feb. 21, 2004) [hereinafter Additional Changes ].
[114] Miller & Longtin, supra note 12.
[115] BRS, Permitting Genetically Engineered Plants That Produce Pharmaceutical Compounds , at http:/www.aphis.usda.gov/lpa/pubs/fsheet_faq_notice/fs_biotechpermitgenetic.html (last visited Feb. 21, 2004).
[116] Additional Changes , supra note 112.
[117] Additional Changes , supra note 112.
[118] 42 U.S.C. §4332 (2004).
[119] Draft Guidance for Industry , supra note 103.
[120] Biologics and human drugs are regulated by FDA’s Center for Biologics Evaluation and Research (CBER) and Center for Drug Evaluation and Research (CDER) respectively, under the authority of the Public Health Service Act (PHS Act) (42 U.S.C. §262 et seq .) and the federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. §301 et seq. ). New animal drugs and animal feeds containing new animal drugs are regulated by FDA’s Center for Veterinary Medicine (CVM) under the authority of the FD&C Act.
[121] Draft Guidance for Industry , supra note 103.
[122] Environmental Effects of Transgenic Plants , supra note 99.
[123] The coalition included Center for Food Safety, EarthJustice, Friends of the Earth, KAHEA, and Pesticide Action Network North America.
[124] USDA Tightens Regulation of Biotech Plant Trails (Top Biotech Stories of 2003) , FOOD CHEMICAL NEWS , Jan. 5, 2004, at 26 [hereinafter USDA Tightens Regulation ].
[125] Rewrite , supra note 1.
[126] First Steps , supra note 104.
[127] Taylor & Tick, supra note 51, at 1.
[128] Environmental Effects of Transgenic Plants , supra note 99.
[129] Committee on Environmental Impacts Associated with Commercialization of Transgenic Plants, Board on Agriculture and Natural Resources, Division of Earth and Life Sciences, National Research Council, Biological Confinement of Genetically Engineered Organisms , available at http://www.nap.edu/books/ 0309090857/html (2004).
[130] Redick, supra note 47, at 128.
[131] Phillip B.C. Jones, Litigation in the Wind , INFORMATION SYSTEMS FOR BIOTECHNOLOGY NEWS REPORT, available at http://www.isb.vt.edu/news/2002/apr02.pdf (April 2002), at 10.
[132] In re StarLink Corn Products Liability Litigation , 212 F.Supp.2d 828 (N.D. Ill. 2002).
[133] Robert Schubert, Monsanto Still Suing Nelsons, Other Growers , CROPCHOICE NEWS , May 21, 2001, available at http://www.cropchoice.com/leadstry.asp?recid=326 .
[134] Jones, supra note 130, at 10.
[135] Martin v. Reynolds Metals Co ., 342 P.2d 790, 792 (Or. 1959).
[136] Although the old view limited trespass to direct intrusions (saving indirect intrusions for nuisance claims), the modern view is that whether the invasion is “direct or indirect is immaterial in determining” whether trespass has occurred. See Lunda v. Matthews , 613 P.2d 63, 66 (Or. Ct. App. 1980) (citing Martin v. Union Pac. R.R ., 474 P.2d 739 (Or. 1970)).
[137] Lunda , supra note 135, at 66.
[138] Borland v. Sanders Lead Co ., 369 So. 2d 523, 530 (Ala. 1979).
[139] Martin v. Reynolds Metals Co ., supra note 134, at 794.
[140] Note that the initial step of identifying defendant(s) may be difficult due to the fact that the location of many biopharm plots are undisclosed and even protected as “confidential business information” (CBI). Thus, non-GMO and organic farmers may not even know that their neighbors are growing biopharm varieties until they discover genetic contamination in their own crops.
[141] This is may often be the case because there not yet many biopharmers currently throughout the U.S.; currently, biopharming is taking place at a relatively small scale.
[142] Richard A. Repp, Biotech Pollution: Assessing Liability for Genetically Modified Crop Production and Genetic Drift , 36 IDAHO L. REV. 585, 603-604 (2000).
[143] Class action suits have already been launched against companies such as Aventis and Monsanto regarding non-biopharm GM contamination.
[144] Drew L. Kershen, Legal Liability Issues in Agricultural Biotechnology , National Agricultural Law Center, available at http://www.nationalaglawcenter.org/assets/article_kershen_biotech.pdf (Nov. 2002), at 5-6.
[145] Martin v. Reynolds Metals Co ., supra note 134, at 794.
[146] Id. at 797.
[147] Kershen, supra note 143, at 7.
[148] Kershen, supra note 143, at 6.
[149] Fuchser v. Jacobsen , 290 N.W.2d 449, 452 (Neb. 1980).
[150] RESTATEMENT (SECOND) OF TORTS §282 (1965).
[151] Maryland Heights Leasing, Inc., v. Mallinckrodt, Inc ., 706 S.W.2d 218, 223 (Mo. Ct. App. 1986).
[152] Kershen, supra note 143, at 10.
[153] Id. at 10-11.
[154] Graham v. Canadian Nat'l Ry. Co ., 749 F.Supp. 1300, 1318 (D. Ver. 1990).
[155] Sterling v. Velsicol Chemical Corp ., 855 F.2d 1188, 1199- 1201 (6th Cir. 1988).
[156] J.W. Looney, Rylands v. Fletcher Revisited: A Comparison of English, Australian and American Approaches to Common Law Liability for Dangerous Agricultural Activities , 1 DRAKE J. AGRIC. L. 149, 160-161 (1996).
[157] RESTATEMENT (SECOND) OF TORTS §520 (1977).
[158] Langan v. Valicopters , Inc., 567 P.2d 218 (Wash. 1977).
[159] Id. at 222.
[160] Note that although Langan has been called a pesticide “drift” case, the pesticide did not actually float by itself into the plaintiff’s land. Rather, the defendant had actually flown over the organic farmer’s property with the pesticide spray on. Hence, whether courts will look to Langan for guidance may also depend on whether they consider the short-term chemical drift in Langan sufficiently analogous to the long-term process that would be required for genetic drift (i.e., “long term” because genetic contamination requires cross-pollination followed by the growth of cross-bred offspring, all of which is not as immediate as the instant contamination of organic crops by chemical pesticides). See Jones, supra note 130, at 11.
[161] Repp, supra note 141, at 619.
[162] Robert F. Blomquist, Applying Pesticides: Toward Reconceptualizing Liability to Neighbors for Crop, Livestock and Personal Damages from Agricultural Chemical Drift , 48 OKLA. L. REV. 393, 405 (1995).
[163] RESTATEMENT (SECOND) OF TORTS §524A (1977).
[164] Presumably, if plaintiff organic farmers succeed with this generalizing argument, their damages may be limited to only the lost profits associated with contaminated conventional food crops, and thus may not include the market premium usually captured by organic food crops.
[165] Borland , supra note 137, at 530.
[166] RESTATEMENT (SECOND) OF TORTS §822 (1979).
[167] See, e.g ., Lunda , supra note 135; see also Jewett v. Deerhorn Enter. Inc ., 575 P.2d 164, 167-68 (Or. 1977).
[168] Repp, supra note 141, at 606.
[169] RESTATEMENT (SECOND) OF TORTS §827 (1979).
[170] RESTATEMENT (SECOND) OF TORTS §828 (1979).
[171] California Orange Co. v. Riverside Portland Cement Co ., 195 P. 694 (Cal. Dist. Ct. App. 1920).
[172] See , e.g., Boomer v. Atlantic Cement Co., Inc ., 257 N.E.2d 870 (N.Y. Ct. App. 1970).
[173] Id .
[174] Repp, supra note 141, at 612-613.
[175] Daniel P. Larsen, Combating the Exotic Species Invasion: The Role of Tort Liability , 5 DUKE ENVTL. L. & POL'Y F. 21, 41 (1995) (quoting City of Phoenix v. Johnson , 75 P.2d 30, 34 (Ariz. 1938)).
[176] RESTATEMENT (SECOND) OF TORTS §821C (1979).
[177] Kershen, supra note 143, at 19.
[178] Redick, supra note 47, at 138.
[179] In re StarLink , supra note 131, at 837.
[180] Id. at 835.
[181] Id. at 848.
[182] RESTATEMENT (SECOND) OF TORTS §821B (1979).
[183] RESTATEMENT (SECOND) OF TORTS §821B cmt. f (1979).
[184] RESTATEMENT (SECOND) OF TORTS §821B cmt. i (1979).
[185] Kershen, supra note 143, at 22.
[186] Id. at 20.
[187] To prevent damages from forcing biopharmers into bankruptcy, and to also ensure defendants can actually collect damages, liability insurance coverage could be mandated by either federal regulations or contracts. Or, biopharmers could be required to contribute to a “superfund” that would compensate defendants for harm suffered.
[188] Pharmacorn , supra note 11.
[189] Scientific Panel , supra note 46.
[190] Manufacturing Drugs , supra note 45, at 52.
[191] Pharmacorn , supra note 11.
[192] Pharming the Field , supra note 28, at 32.
[193] See Pharmacorn , supra note 11; see also Scientific Panel , supra note 46.
[194] Due to a political backlash, particularly from Iowa Senators Charles Grassley and Tom Harkin, BIO quickly abandoned the proposed moratorium in December 2002.
[195] Pharmacorn , supra note 11.
[196] Pharmacorn , supra note 11.
[197] Pharming Rubber Trees , at http://www.isb.vt.edu/articles/apr9511.htm (Apr. 1995).
[198] Pharmacorn , supra note 11.
[199] Walsh, supra note 9.
[200] Miller & Longtin, supra note 12.
[201] Daniell, supra note 35.
[202] Miller & Longtin, supra note 12.
[203] Cole, supra note 57.
[204] Giddings et al., supra note 15, at 1154.
[205] Stephen Clapp, Bush Administration Considers Regulating PMPs as Unapproved Food Additives , FOOD CHEMICAL NEWS , June 30, 2003, at 16 [hereinafter Bush Administration ].
[206] Daniell, supra note 35.
[207] Bush Administration , supra note 204.
[208] PMIs, on the other hand, would probably have a lower likelihood of gaining GRAS status.
[209] Bush Administration , supra note 204.
[210] USDA Tightens Regulation , supra note 123.
[211] Note that this incentive for “mutual policing” could be reinforced by imposing joint and several liability on all participants in the entire chain of commerce.
[212] Fay & Phillips, supra note 73.
[213] An illustrative example of redundancy is Monsanto’s approach. Since the company has invested heavily in it antibody-producing GM corn crops, it is going the extra mile in terms of compliance. Monsanto simultaneously uses multiple measures to prevent gene drift: (1) larger buffer zones from other maize crops, (2) male plant sterilization to prevent pollen production, (3) daily satellite monitoring of adjacent fields for maize plants, (4) separate harvesting and processing machinery, and (4) ensuring that no maize is planted in the same fields for two years by growing a herbicide-resistant cotton cultivar resistant to a herbicide toxic to maize plants. See Cole, supra note 57.
[214] Randy Fabi, USDA Mulls Program Verifying Bio-Free U.S. Crops , REUTERS , Aug. 6, 2002, available at http://www.organicconsumers.org/gefood/segregation080802.cfm .
[215] The cost of implementation would be significant, but could be reduced by the use of “grower districts or regional moratoria (e.g., BIO’s proposed voluntary moratorium in the Corn Belt) to isolate biopharm crops to certain geographic areas, separate from food crops. An example of a grower district is the entire state of California, in which GM rice is banned. Specifically, the California state legislature passed Assembly Bill 2622, which established California-specific standards for segregating different rice varieties while imposing fees on the sale of rice seeds that pose economic risks. See CAL. FOOD & AGRIC. CODE §§55050-55052, 55060-55063 (West 2004).
[216] Redick, supra note 47, at 119.
[217] For an example of “eco-terrorism,” consider the purported actions of the Earth Liberation Front. This a radical group that claims to have set fires to a Seattle genetics research laboratory and an Oregon tree nursery, causing more than $3 million in damage. See Zitner, supra note 34.
[218] Manufacturing Drugs (Executive Summary) , supra note 6, at 8.
[219] Biotech Chief , supra note 7.
[220] Redick, supra note 47, at 142.