After the widespread adoption of pasteurization and refrigeration, dairy foods transitioned from being a relatively risky foodstuff to one of the safest staple commodities in our food supply. In fact, when producers strictly follow the protocols and approaches prescribed by the U.S. Department of Agriculture (USDA) Grade A Pasteurized Milk Ordinance, Hazard Analysis and Critical Control Points (HACCP), and other Good Manufacturing Practices (GMPs), the only common "risk" dairy could be said to present is an upset stomach for those with lactose intolerance.

Of course, even our modern food supply is not perfect, and mistakes fall through the cracks. Raw milk and fresh cheeses can contain pathogens such as Listeria, mislabeling can result in undeclared allergens, and dairy farms themselves may be a source of contamination for other agricultural products through runoff.^1,2 However, our modern systems have long guaranteed a safe supply of milk and dairy to the masses.

That said, there are several emergent issues facing the safety of dairy. One is that the current zeitgeist around the supposed benefits of raw milk has resulted in a relative surge in popularity, with multiple states legalizing its sale and increased reports of outbreaks connected to raw milk consumption.³ Secondly, H5N1 (also referred to as highly pathogenic avian flu, or HPAI) has reportedly been infecting dairy herds across multiple states since 2024, posing a potential public health threat.⁴ It is still largely unknown what impacts H5N1 could have on the dairy industry and public health at large. It is unlikely that viral particles would survive pasteurization in any meaningful capacity and impact consumers;⁵ however, dairy workers have reportedly contracted the virus from herds, and active viruses have been found in raw milk.^4,6 Although still at an early stage, H5N1 worries health officials due to its potential to mutate and spread. This is likely no surprise to most, as the COVID-19 pandemic is theorized to be zoonotic in origin, and its impact is still fresh in our minds.

As safe as dairy foods are in themselves, the industry does pose indirect and broader safety implications aside from H5N1. For example, millions of kilograms of antibiotics are distributed for use in livestock every year in the U.S.⁷ The majority of those antibiotics are medically relevant, meaning they have application in treating human disease.⁷ While strict regulations prevent milk that contains antibiotics from entering the supply chain, this widespread use of antibiotics on farms places adaptive pressure on microbes to become resistant to these medications. There have long been consistent warnings from experts on the overuse of antibiotics in agriculture due to this risk. The more we use these drugs at this scale, the higher the likelihood that pathogens will develop resistance and spread across farms and in communities.

Precision Fermentation: An Alternative to Plant-Based Dairy

Despite the overall safety and quality of modern dairy, there has been a growing interest by consumers to move away from this staple of our food supply. Whether due to taste preference, ethical concerns, or because of dairy's significant impact on the environment, traditional dairy has had tough competition with plant-based dairy replacements for market share in recent years.⁸ However, these plant-based "milks" (soy, oat, almond, etc.) and cheeses do not compare to dairy milk's sensory, nutritional, or functional properties. Mammalian milk has unique characteristics that have led to its dominance in Western cuisine for centuries. These qualities mostly stem from the casein and whey proteins present in bovine milk. These proteins are "complete," providing all essential amino acids in the correct ratios for human nutrition. Additionally, whey has many functions in food as a foaming and emulsifying agent, and casein provides the stretch and pull essential to many cheeses. Plant-based alternatives have difficulty matching the nutritional and functional properties that make milk so valuable as a component of our culinary culture.

As a result of plant-based products' failure to replicate the complexity of true dairy, a potential new player in the dairy sector has entered the market. These products formulate dairy food alternatives using casein and whey protein ingredients produced not by animals, but through a process called precision fermentation. This is a relatively new term coined for a process that has actually been in use for decades.

The principle of precision fermentation is to use microorganisms as "cellular factories" to produce ingredients of interest. This differs from traditional fermentation, which is used to modify or transform a food (i.e., the food in question acts as a growth substrate and also becomes the final product or ingredient). The goal of precision fermentation, however, is to isolate specific molecular components of interest that are produced by the microbial host, regardless of what is used as the growth medium. Precision fermentation as a food production technique has been used for decades to manufacture ingredients such as flavors, vitamins, enzymes, saccharides, and others. As technology advanced, scientists gained the ability to genetically engineer microbes, allowing for the production of bespoke compounds and, thus, recombinant chymosin was born. This was the first widespread use of a recombinant protein in food production—ironically also with a dairy application, as a way to make cheese by curdling milk without having to use naturally harvested rennet.

Developments in genetic technology have created a boom in the use and potential applications of precision fermentation. As such, governments are now faced with regulating the safety aspects of these novel ingredients as they become more commonplace. One of the difficulties regulators are currently facing is the lack of a commonly accepted definition of precision fermentation.⁹ One simple and straightforward working definition offered by the European Food Safety Authority (EFSA) is "the use of engineered microbial cell factories in the production of food ingredients."⁹ The key word is "engineered," as the concept of using genetically modified (rather than wildtype) organisms to produce ingredients has certain connotations in the public mind, as well as safety implications in some ways. Therefore, the regulatory landscape of modern precision fermentation technology is rapidly adapting to pave the way for novel food products to reach the market.

In the context of dairy, proteins are the key component that provide most of the nutritional, functional, and sensory benefits, and they also happen to have the highest market value compared to the other two macronutrients. A number of companies globally are already producing recombinant casein and whey proteins for various applications in both dairy and non-dairy food sectors. In some regions, currently available products that contain recombinant dairy proteins include ice cream, cheese, and animal-free milk beverages. Additionally, these fermentation-derived proteins can be used in a variety of food categories and applications as a functional ingredient. However, the distribution of these products is still limited as the technology continues to scale up and regulatory bodies across the globe attempt to set frameworks for approval and monitoring of these products.

Safety Implications of Novel Precision Fermentation Ingredients

To understand the safety implications of these novel precision fermentation ingredients, the technology that manufacturers use must first be explained. To produce a protein of interest, developers will select an organism capable of synthesizing it (preferably at high volumes, for the sake of operating costs). Model organisms such as E. coli, B. subtilis, and Saccharomyces have been engineered to produce recombinant dairy proteins; however, most current manufacturers generally use filamentous fungi such as Aspergillus spp. or Trichoderma reesei,^10–13 as their capability for extracellular output of proteins is higher, which makes purification and isolation more straightforward. There is a strong preference to use microbes that already have or can obtain Generally Recognized As Safe (GRAS) status from the U.S. Food and Drug Administration (FDA) or qualified presumption of safety (QPS) status from EFSA, as this reduces regulatory approval hurdles for any ingredients produced via precision fermentation.^12,13 The use of these accepted microorganisms reduces the risk of any chemical or biological hazard being introduced by the organism itself, as they are already well characterized.

The biggest and perhaps most important difference between dairy produced via microbes versus animal-sourced dairy is that precision fermentation takes place in a highly controlled manufacturing facility, while traditional dairy comes from a relatively open (and comparatively dirty) farm environment. It may be self-evident that dairy farms are not microbially pristine, especially compared with the closed, sanitized environment of a fermentation facility. As such, precision fermentation has a great advantage in preventing the introduction of adulterants and pathogens.

A well-run fermentation plant will, by design, have stringent controls in place to prevent contamination of bioreactors and protect the quality of the fermentation run, particularly since antimicrobials are strongly discouraged in large-scale, food-grade production runs.¹⁰ Cleanliness, aseptic technique, and environmental monitoring of microorganisms are part and parcel of operating these types of facilities. Therefore, precision fermentation has an inborn favorability toward preventing pathogens and contamination. The record for these products is quite clean; there has yet to be any report of commercially available precision fermentation-derived ingredients being microbially contaminated or being recalled for that reason.^10,14

Perhaps the most significant and unique safety risk posed by novel precision fermentation-derived dairy proteins is that of allergenicity. The proteins produced by engineered microbes are not completely identical to their wildtype counterparts. In the design phase of a recombinant protein, the amino acid sequence may be slightly altered to favor synthesis in the host organism or to improve the functionality of the final protein, which may increase allergenicity.¹⁵ Additionally, the microbial factories themselves do not have identical post-translational modification behavior to mammalian cells, which may also have repercussions on allergenicity.^10,12 In general, it is likely that most allergenic epitopes contained in a dairy protein will remain similar to the wildtype;¹⁰ however, patents have been filed for recombinant dairy proteins that purportedly have reduced allergenicity.¹⁶ Nonetheless, it has been suggested that manufacturers develop specific immunoglobin E (IgE) assays in order to screen for sensitization induced by novel proteins.^12,15,17 Amino acid sequences can also be bioinformatically screened against databases to flag any similarities to known allergens or toxins.^10,12 Finally, it has been suggested that the digestibility of these novel proteins be studied as well, to establish their behavior and fate within the human gastrointestinal tract.^9,12,17

There are potential additional risks associated with precision fermentation-derived ingredients. These mostly involve downstream processes and final purification/isolation of the acellular target molecule. Growth media components, as well as metabolic coproducts including exopolysaccharides, non-target proteins, etc., need to be minimized/eliminated in the final purified product, not only to ensure a quality ingredient for formulation but also to reduce the risk of any adverse sensitivities in consumers.^10–12

Regulatory Frameworks for Precision Fermentation Ingredients

While the safety and risks associated with precision fermentation ingredients appear to be straightforward thus far, the two key concerns at this stage (from manufacturers and regulators alike) are:

1. Developing a standardized and unified international regulatory framework
2. Fostering public confidence in the safety of this unique and relatively new method of food production.^11,12

It will be essential to address both concerns in order for this nascent food sector to grow and become a significant player in our food supply.

Regarding regulatory frameworks, while the concept and principles of precision fermentation have been used in food applications for decades (e.g. rennet, other enzymes, vitamins, flavorings, etc.), we are now reaching a new era of application and prevalence. The wide variety and increasing number of new recombinant proteins and products containing them require regulatory bodies to clarify, adapt, and enhance their methods for monitoring, testing, and approving novel precision fermentation foods and ingredients. At present, nations and jurisdictions are operating on aging policies and standards that may differ significantly between regions and across borders. Importantly, regulatory bodies differ in their approach to approving novel precision fermentation ingredients. In the U.S., companies "self-affirm" their final product for GRAS status and submit safety dossiers to FDA in the hope of receiving a "No Questions" letter, which implies approval of the product. This has already been granted to multiple precision fermentation ingredients.¹¹

By contrast, any genetically modified-derived food in the EU undergoes an extensive safety evaluation by EFSA that includes analysis of the organism itself, as well as genomic data and other elements.¹¹ To date, EFSA has not approved any precision fermentation-derived ingredients.¹¹ This demonstrates the disparate nature of these separate approval processes and safety evaluations. The differences in existing regulatory frameworks can be a significant hurdle for producers looking to enter a global market. (For further reading on a European perspective of the toxicological risk analysis of dairy proteins specifically, Fytsilis et al. published a thorough 2024 paper on this topic.¹⁷)

With the aim of modernizing and adapting regulatory frameworks for novel precision fermentation ingredients and applications, EFSA held a Colloquium in 2024 on cell culture-derived foods and ingredients.⁹ Additionally, the Food and Agriculture Organization of the United Nations (FAO) released a report in 2025 that provided a comprehensive summary of existing regulations for precision fermentation foods and ingredients globally, along with the factors that should be considered as nations develop more robust regulatory frameworks for this nascent food sector.¹² There is great interest in these regulatory developments as startups aim to launch their flagship products and established companies expand their product lines in the coming years.

Building Public Trust for Precision Fermentation

The second major concern for precision fermentation's future, particularly for manufacturers, is building public trust in these novel foods and ingredients. Most of the food industry is aware of the longstanding skepticism and misconceptions held by the public regarding foods and ingredients derived from genetically modified (i.e., bioengineered) organisms. Despite the continually demonstrated safety of these foods and the lack of evidence for purported health risks, the hesitance persists. Experts have encouraged companies to establish stringent and thorough testing and monitoring protocols to assuage potential consumer safety concerns surrounding these novel foods.^11,12

Despite widespread openness to the concept of alternative protein sources in the food supply, precision fermentation producers would still benefit from a robust body of evidence supporting the safety of their products in order to establish public confidence and acceptance.¹¹ It should also be noted, as with any other food or ingredient, that clarity in traceability and labeling for precision fermentation ingredients is essential for their success and acceptance, not only from the consumers' perspective but also as part of a well-functioning and safe supply chain.

In summary, the use and safety of fermentation-derived ingredients in foods have been long established as manufacturers abide by existing regulatory policies and GMPs. Fermentation has been generally accepted as a safe means of producing food. However, as a large number of novel recombinant protein ingredients enter the market in a variety of applications, additional safety and risk assessments are warranted to address concerns of potential emergent allergenicity and/or toxicity. Regulatory bodies have begun the process to adapt existing regulations and to develop new, preferably unified, guidelines.

As this is a rapidly evolving topic, no definitive resource yet exists on the safety and regulatory landscape of precision fermentation-derived foods and ingredients. The previously mentioned and cited 2025 FAO report and notes from the 2024 EFSA Colloquium contain extensive expert opinion and perspectives.^9,12 Additionally, resources from the Good Food Institute and Ronchetti et al. contain further information.^11,18 Overall, the advent of precision fermentation-derived ingredients is an exciting prospect for the future of alternative protein sources, as we aim to feed a growing global population safely and sustainably.

References

1. Dogan, O.B., M.G. Flach, M.F. Miller, and M.M. Brashears. "Understanding Potential Cattle Contribution to Leafy Green Outbreaks: A Scoping Review of the Literature and Public Health Reports." Comprehensive Reviews in Food Science and Food Safety 22, no. 5 (July 2023): 3506–3530. https://doi.org/10.1111/1541-4337.13200.
2. U.S. Centers for Disease Control and Prevention (CDC). "How Listeria Spread: Soft Cheeses and Raw Milk." Listeria Infection (Listeriosis). January 16, 2025. https://www.cdc.gov/listeria/causes/dairy.html.
3. CDC. "Research Anthology: Raw Milk." Public Health Law. May 16, 2024. https://www.cdc.gov/phlp/php/publications/research-anthology-raw-milk.html.
4. CDC. "Current Situation: Bird Flu in Dairy Cows." Avian Influenza (Bird Flu). July 7, 2025. https://www.cdc.gov/bird-flu/situation-summary/mammals.html.
5. U.S. Food and Drug Administration (FDA). "Investigation of Avian Influenza A (H5N1) Virus in Dairy Cattle." Current as of March 14, 2025. https://www.fda.gov/food/alerts-advisories-safety-information/investigation-avian-influenza-h5n1-virus-dairy-cattle.
6. Schnirring, L. "California Reports Avian Flu in Retail Raw Milk Sample." Center for Infectious Disease Research and Policy (CIDRAP). University of Minnesota Twin Cities. https://www.cidrap.umn.edu/avian-influenza-bird-flu/california-reports-avian-flu-retail-raw-milk-sample.
7. Dall, C. "New FDA Report Shows More Antibiotics Being Sold for Food Animals." Center for Infectious Disease Research and Policy (CIDRAP). University of Minnesota Twin Cities. https://www.cidrap.umn.edu/antimicrobial-stewardship/new-fda-report-shows-more-antibiotics-being-sold-food-animals.
8. Harfmann, B. "The Competition Between Dairy Milks and Plant-Based Milk Heats Up." Dairy Foods. June 24, 2024. https://www.dairyfoods.com/articles/97384-the-competition-between-dairy-milks-and-plant-based-milk-heats-up.
9. Afonso, A.L., W. Gelbmann, A. Germini, E.N. Fernández, L. Parrino, G. Precup, and E. Ververis. European Food Safety Authority (EFSA). "EFSA Scientific Colloquium 27: Cell Culture‐Derived Foods and Food Ingredients." EFSA Supporting Publications 21, no. 3 (March 2024). https://doi.org/10.2903/sp.efsa.2024.EN-8664.
10. Tan, Y.Q.; H.C. Ong, A.M.H. Yong, V. Fattori, and K. Mukherjee. "Addressing the Safety of New Food Sources and Production Systems." Comprehensive Reviews in Food Science and Food Safety 23, no. 3 (May 2024): e13341. https://doi.org/10.1111/1541-4337.13341.
11. Eastham, J.L. and A.R. Leman. "Precision Fermentation for Food Proteins: Ingredient Innovations, Bioprocess Considerations, and Outlook—A Mini-Review. Current Opinions in Food Science 58 (August 2024): 101194. https://doi.org/10.1016/j.cofs.2024.101194.
12. Sturme, M., J. van der Berg, and G. Kleter. "Precision Fermentation With a Focus on Food Safety." Food and Agriculture Organization of the United Nations (FAO). 2025. https://doi.org/10.4060/cd4448en.
13. Augustin, M.A., C.J. Hartley, G. Maloney, and S. Tyndall. "Innovation in Precision Fermentation for Food Ingredients." Critical Reviews in Food Science and Nutrition 64, no. 18 (2024): 6218–6238. https://doi.org/10.1080/10408398.2023.2166014.
14. Jin, J., H.M.W. Den Besten, I.M.C.M. Rietjens, and F. Widjaja-van Den Ende. "Chemical and Microbiological Hazards Arising from New Plant-Based Foods, Including Precision Fermentation-Produced Food Ingredients." Annual Review of Food Science and Technology 16, no. 1 (2025): 171–194. https://doi.org/10.1146/annurev-food-111523-122059.
15. Boukid, F., S. Ganeshan, Y. Wang, M.Ç. Tülbek, and M.T. Nickerson. "Bioengineered Enzymes and Precision Fermentation in the Food Industry." International Journal of Molecular Sciences 24, no. 12 (2023): 10156. https://doi.org/10.3390/ijms241210156.
16. Bhatt, V., L. Clark, T. Geistlinger, and J. Lin. "Hypoallergenic Recombinant Milk Proteins and Compositions Comprising the Same." U.S. Patent US20230106635A1. April 6, 2023. Google Patents. https://patents.google.com/patent/US20230106635A1/en?oq=us+2023%2f0106635+A1.
17. Fytsilis, V.D., M.J.E. Urlings, F.-J. Van Schooten, A. De Boer, M.F. Vrolijk. "Toxicological Risks of Dairy Proteins Produced through Cellular Agriculture: Current State of Knowledge, Challenges and Future Perspectives." Future Foods 10 (December 2024): 100412. https://doi.org/10.1016/j.fufo.2024.100412.
18. Ronchetti, F., L. Springer, and K.P. Purnhagen. The Regulatory Landscape in the EU for Dairy Products Derived from Precision Fermentation: An Analysis on the Example of Cheese. SpringerBriefs in Law. Springer Nature Switzerland, 2024. https://doi.org/10.1007/978-3-031-49692-9.

Drew Carter, Ph.D. is the Communications Coordinator for the Department of Food Science and Nutrition at the University of Minnesota Twin Cities' College of Food, Agricultural, and Natural Resource Sciences. He holds a Ph.D. in Food Science and Nutrition from the University of Minnesota and B.A. degrees in Biology and Chemistry from Bemidji State University. His research interests include cellular agriculture, precision fermentation, microbiomes, flavor and sensory evaluation, and science communication.