anesthetic residues would remain pertinent. If animals genetically engineered for xenotransplantation, but not used for that purpose, were presented for entry into the food chain, the food safety of such animals also would have to be evaluated based on protocols developed for evaluating other genetically engineered animals.

Animals might be genetically engineered to produce non-food products in their milk or eggs. Half of the genetically engineered population will be male, and will not be directly useful for production of heterologous proteins in, for example, milk or eggs. It is likely that companies producing such animals will seek early entry of males that are transgenic, but incapable of producing milk or eggs, into the food chain. In addition, companies might want to enter females that are “no takes”, which do not express high levels of the product of interest, or that have reached the end of their productive lives, into the human food supply. The safety of food products from such animals that were culled from transgenic lines might present concerns.

Numerous experiments have shown that the level and specificity of transgene expression in an animal is predictable only to a limited extent, probably because all the factors affecting gene expression have not yet been identified (Houdebine, 2000). Transgenes might be expressed at a low level in various tissues in which the promoter is not expected to be active. Such ectopic expression might be due to genomic position effects attributable to the action of neighboring enhancer elements. In addition, ectopic expression might result from basal-level transcription at the site of integration (Ashe et al., 1997; Travers, 1999). Recombinant proteins whose expression is driven by regulatory elements directing expression in mammary glands have been observed in the blood of transgenic animals during lactation (Bishoff et al., 1992; Devinoy et al., 1994; Thepot et al., 1995). The presence of transgene products in blood might result from leakage of the mammary epithelium or from secretion at the apical side of mammary cells. For example, although the promoter from the whey acidic protein (WAP) gene has been used to direct expression of a transgene in mammary tissue, and some concentration of WAP normally is found in the blood of lactating animals (Grabowski et al., 1991). Hence, through bioactivity, allergenicity, or toxicity pathways, ectopic gene expression might directly affect the safety of food products derived from tissues, sexes, or life stages of transgenic animals where transgene expression is not expected. In some cases, recombinant proteins produced in milk have deleterious effects on mammary gland function (Bishoff et al., 1992; Shamay et al., 1992; Bleck et al., 1995; Ebert et al., 1994) or on the transgenic animals more generally (Burdon et al., 1991; Reddy et al., 1991; Jhappan et al., 1993; Devinoy et al., 1994; Hennighausen et al., 1994; Thepot et al., 1995; Massoud et al., 1996; Litscher et al., 1999). These effects might stem from ectopic expression of the transgene or from transfer of the recombinant proteins from mammary gland to blood. Animals with variable levels or ectopic expression of the transgene presumably

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