1. Environmental Safety Assessment Eric Silberhorn, PhD, DABT

2. Describes the animal, construct, and proposed claim Are there sequences that are likely to contain potential hazards to the animal, humans, or animals consuming food from that animal, or the environment? e.g., does the construct contain mobilizable sequences from viruses that may be endemic in that species? Does the insertion of the rDNA construct pose a hazard to the animal, humans, other animals by feed, or the environment? Are the genotype or phenotype changing over the product lifespan in a way that would affect the risks associated with the product? Is there a plan in place to monitor those changes? What are the direct and indirect risks posed to the GE animal? (e.g., can surveying the health and other phenotypic characteristics of the animal inform us with respect to risk to the animal and potential human food safety concerns?) What are the risks of direct or indirect adverse outcomes associated with the consumption of the GE animal as food or feed? Direct or indirect effects from introduction of the GE animal into the environment? Environmental Safety What hazards/risks have been identified in the hierarchical review?

3. Statutory/Regulatory Requirements Sponsor must submit Environmental Assessment/supporting data under INAD/NADA National Environmental Policy Act (NEPA) requirement triggered by “agency action” EA  FONSI? (finding of no significant impact) If no FONSI, EIS (environmental impact statement)

4. Environmental Assessment: General Risk Questions For a specific GE animal (population) containing a specific rDNA construct…. Risk(s) under conditions of use/free release? Likelihood of escape/free release? Containment/redundancy Potential adverse outcomes associated with escape/free release? Considered in context of appropriate comparator on a case-by-case basis.

5. Source(s) Escape or Introduction Able to Survive Impact on Target Resources in Accessible Environments (habitats, wildlife) Dispersion Direct and Indirect Effects Accessible Environments Able to Reproduce Establishment Spread of Transgene(s) Wild Conspecifics Feral Relatives Physical Containment Biological Containment Net Fitness Conceptual Model for Risk Assessment

6. This previous slide is a flow diagram describing the steps that a risk assessor might follow in order to understand the risks associated with an environmental release of GE animal. The flow diagram begins with understanding the Source (the physical location in which the GE animal is being housed (e.g., farm, hatchery)). This includes a complete description of the physical containment that has been imposed on that source. The next step considers either intended release or the likelihood of an escape from containment. In the next step, the risk assessor evaluates the environments accessible to the released or escaped GE animal. The ability to survive comprises the next steps, followed by an assessment of either dispersion or the ability for that animal to reproduce considering any applicable biological confinement. If the animal is capable of reproducing, the next point of evaluation looks at the spread of the transgene(s) via horizontal transfer to wild conspecifics or to feral relatives. Another path from the ability to reproduce involves an evaluation of the ability of the GE animal to become established in the local environment. Finally, the assessment ends with a consideration of the potential direct and indirect effects that the released or escaped GE animal can cause to target resources in the accessible environments (e.g., habitats and on wildlife).

7. Prioritization of Concerns Consideration of the following factors: 1. Ability of GE animal to disperse into diverse communities upon release or escape 2. “Fitness” of GE animal within the receiving ecosystem 3. Stability and resiliency of the receiving community Overall concern is a product (and not the sum) of these three variables

8. Consequences of Introduction, Escape, and Dispersion Depends on Physical locations of use or release Extent of containment (if applicable) Physical Biological (sterility, triploidy, monosex) Geographical Niche limitations Domestication of species (ability to become feral) Mobility of species

9. Fitness* Genetic contribution by an individual’s descendants to future generations of a population Fitness depends on both survival and reproduction Net fitness components include Juvenile and adult viability Age at sexual maturity Female fecundity/male fertility/mating success * These characteristics are used to assess fitness regardless of an animal’s GE status

10. Fitness Does incorporation of the rDNA construct alter the animal’s fitness? Potential examples of altered fitness Disease resistance Temperature tolerance Growth factors / hormones Nutrient/carbohydrate utilization

11. Direct and Indirect Effects Pathogen / disease transfer Genetic disturbance Resource competition Displacement Habitat destruction Predation Population changes Community/Ecosystem disruptions

12. Potential Environmental Risks HazardRisk Use of viral sequences, including vectors (Characterized in Molecular Characterization steps) Increased probability of new pathogenic recombinants Traits increasing species fitness or adaptation (Characterized in Phenotypic Characterization) Increased probability of disruption of existing ecosystems due to establishment of a GE animal in the environment Altered population dynamics due to horizontal transfer of gene construct(s) (Likelihood of transfer part of Molecular Characterization steps) Specific risk is a function of the nature of the trait

13. Environmental Assessment General Risk Questions Risk associated with the goats in confinement? Likelihood of escape? Potential adverse outcomes associated with escape? Conclusions No environmental risks from confined rhAT goats, wastes Escape unlikely (multiple levels of confinement, security, ID) In event of escape without recapture, survival, reproduction, population establishment is highly unlikely Note: EA/FONSI posted http://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummari es/UCM118087.pdf http://www.fda.gov/downloads/AnimalVeterinary/DevelopmentApprovalProcess/GeneticEngineering/Genetic allyEngineeredAnimals/UCM163814.pdf