Risk assessment and risk management of transgenic pharmaplants
by Dr. Robert K. D. Peterson, Montana State University, Bozeman, Montana, USA. E-mail: [email protected]
Pharmaceuticals using genetic engineering have been made through protein expression in bacterial, fungal, and mammalian cell cultures. Biotechnology is currently evolving to produce more complex and diverse pharmaceutical proteins in plants. Using plants offers the promise of large-scale production of therapeutic proteins.
Production of pharmaceutical proteins in plants represents a paradigm shift in the production of pharmaceuticals and biologics, but also in the uses of products formerly limited to food or feed uses. The plant (or food) is not the final pharmaceutical product, just as microbial or yeast pharmaceutical production systems do not represent the final product. Rather, the plant represents just one step in a complex, multi-step pharmaceutical production process. Therefore, most processes in the production of pharmaceuticals will (or should) follow traditional regulatory requirements.
However, the production of these proteins in plants in the environment introduces several unique challenges from regulatory and risk assessment perspectives. Most of these challenges arise from the simple fact that the plants are being produced in the open environment, a unique aspect of pharmaceutical manufacturing. In a field environment, special containment is possible and amenable to strict regulation, but containment is inherently less certain compared with traditional pharmaceutical manufacturing processes. Because of this, questions of potential intraand inter-species gene flow, allergen exposure to the public, and non-target organism exposure come into play.
Regardless of how specific regulatory activities and responsibilities unfold, the human and ecological risks associated with cultivating these plants in the environment must be assessed using the most robust, transparent science-based methods available. The established paradigm of risk assessment offers the best approach for assessing these risks.
The risk assessment framework that is practiced most frequently today follows a logical, stepwise process that includes the following procedures: (1) problem formulation, (2) hazard identification, (3) dose-response relationships, (4) exposure assessment, and (5) risk characterization. Hazard and dose are considered in juxtaposition with exposure to determine risk or to determine what additional data are needed to calculate or refine risk estimates. For chemical risk assessments in which a chemical, such as a pesticide, is disseminated into the environment, the exposure assessment step typically is crucial to adequately characterizing risk. Conversely, the problem formulation and hazard identification steps arguably are most important when considering risk from plant-based pharmaceuticals (see journal articles listed below for more information).
The problem formulation step establishes the goals, breadth, and focus of the assessment. Questions that might be addressed during the problem formulation stage include: What is the stressor or activity causing harm?; What are the potential ecological and human health effects?, and; What are the potential exposure scenarios and routes of exposure? The hazard identification step is the act of determining what the hazard is and its ability to cause harm.
The answers to the above questions and actions might be self evident for an environmental contaminant, such as a pesticide, but they are hardly self evident for many plants expressing certain pharmaceutical proteins. For example, what is the stressor in a system in which a potato plant expresses a bovine-specific antigen that will be used as an oral veterinary vaccine? Does the recombinant protein have the ability to cause harm to humans or the environment? Is the potato plant itself hazardous? How do we identify the hazard? Should we conduct a battery of toxicity tests on a large group of non-target species irrespective of our knowledge of the specificity of this antigen or the possibility of exposure? See Shama and Peterson 2008a, b (see below) for more information on potential effects and exposure.
Because of their specificity, lack of toxicity, and therapeutic or disease prevention capabilities, many pharmaceutical proteins that will be produced in plants will challenge our ability to define an environmental hazard. The staggering variety of recombinant proteins that can be expressed by plants demands that the risks associated with them be assessed on a case-bycase basis. A case-by-case analysis fits well within the stepwise nature of risk assessment. Risk assessment is amenable to both quantitative and qualitative approaches. The ability to describe risk qualitatively will probably be important for plant-based pharmaceutical production because of difficulties in establishing a hazard with the highly specific proteins that could be expressed. However, the ability to describe these risks quantitatively is more important for comprehensive societal decision making and communication.
References provided by the author
Shama LM, Peterson RKD (2008a) Assessing Risks of Plant-Based Pharmaceuticals: I. Human Dietary Exposure. Human and Ecological Risk Assessment 14: 179-193. (
reprint)
Shama LM, Peterson RKD (2008b) Assessing Risks of Plant-Based Pharmaceuticals: II. Non-Target Organism Exposure. Human and Ecological Risk Assessment 14: 194-204. (
reprint)
Peterson RKD, Arntzen CJ (2004) On risk and plant-based biopharmaceuticals. Trends in Biotechnology 22: 64-66. (
reprint)
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