Bioavailability and Pharmacodynamics of Eicosapentaenoic Acid and Docosahexaenoic Acid in Soymilk and Commercial Supplements
Phase: EARLY_PHASE1
Conditions: Healthy Diet
Sponsor: Ohio State University Comprehensive Cancer Center

Approval Date: 3/6/2023 
Bioavailability and pharmacodynamics of eicosapentaenoic 
acid and docosahexaenoic acid in soymilk and commercial 
supplements  
 
Principal Investigator: 
Yael Vodovotz, PhD 
Professor, Department of Food Science and Technology 
227 Parker Food Science and Technology Building 
2015 Fyffe Rd. 
Columbus, OH 43210 
Tel: 614-247-7696 
Fax: 614-292-0218 
Email: Vodovotz.1@osu.edu 
 
Co-Investigators: 
Steven Clinton, MD, PhD 
Physician Scientist and Professor 
College of Medicine 
Steven.clinton@osumc.edu  
 
Martha Belury, PhD, RD 
Carol S. Kennedy Professor 
Department of Human Sciences 
Belury.1@osu.edu 
 
Key Personnel: 
Abigail Sommer, MS 
Graduate Student 
Sommer.155@osu.edu 
317-508-7748 

Approval Date: 3/6/2023 
I. 
Objectives 
The goal of this study is to assess if docosahexaenoic acid (DHA) and eicosapentaenoic acid 
(EPA) accumulate in blood lipids to the same extent when consumed as a fortified beverage as 
opposed to a traditional capsule as well as assess compliance to daily consumption, tolerance 
and acceptability of a fortified soymilk beverage. 
It is hypothesized that DHA and EPA levels will be equivalent in erythrocytes after 4 weeks of 
fortified soymilk consumption as compared to commercial capsules. 
We propose the following objectives: 
A. Evaluate the effect of EPA and DHA matrix (beverage or capsule) on accumulation of 
EPA and DHA in lipid pools over 4 weeks of daily consumption. 
1. EPA and DHA levels will be measured in erythrocytes, peripheral blood mononuclear 
cells (PBMC), platelets, and plasma over time. 
B. Assess suitability of soymilk as a delivery vehicle for EPA and DHA. 
1. Compliance will be measured using daily intake logs and the return of empty and full 
bottles of soymilk or remaining capsules 
2. Tolerability will be monitored using a daily symptom journal. 
3. Sensory acceptability will be monitored initially and after 4 weeks of consumption to 
validate long term use of the fortified soymilk. 
 
II. Background and Rationale 
Research shows that fish oil and its component fatty acids EPA and DHA provide health 
benefits such as reducing the risk of cardiac death and lowering inflammation1. Yet a large 
portion of the population is not consuming the recommended amount of fish due to high cost, 
dietary restrictions such as vegetarianism/veganism, concerns about high levels of mercury, 
general dislike, and other factors2. Additionally, to meet the recommendations fish and fish oil 
production present sustainability challenges. A potential alternative is to utilize EPA and DHA 
from algae. Algae oil has performed equally to fish oil in several clinical studies and has been 
demonstrated as safe for consumption3.  These sustainable oils can be added to foods 
increasing the potential for fatty acids to counteract chronic disease and increasing access to 
general consumers.  
Emulsification of omega-3 fatty acids and incorporation into food products have been shown in 
multiple studies to enhance short-term bioavailability of the oil4. This pre-emulsification before 
digestion improves the rate and extent of incorporation into lipid pools4. Some longer term 
studies of 4 weeks showed no difference or bioequivalence between algae or fish oil capsules 
and various fortified foods or microencapsulated oils5–7. However, soymilk has not been 
assessed as a vehicle for EPA and DHA. Therefore, the bioavailability or bioequivalence to 
capsules needs to be measured. This study will offer valuable data showing that algae oil 
consumed in a soymilk matrix has the ability to alter lipid pools in the long term. This study will 
also provide preliminary data including compliance, sensory acceptability, and tolerability, 
validating the use of an algae oil fortified soymilk in future clinical studies.  
Previously, our lab has developed, and optimized EPA and DHA fortified non-dairy plant milk 
beverages utilizing algae oil emulsions (food grade). Soymilk was chosen as the optimal vehicle 
due to its ability to mask some of the algae oil flavor, while maintaining stability of the fatty 

Approval Date: 3/6/2023 
acids. Up to 0.4% algae oil can be added to soymilk with limited changes to overall liking. 
Consumers did not prefer the control samples over 0.4% algae oil samples at statistically 
significant levels, meaning that they did not reject those samples. These samples were 
unflavored and addition of flavoring such as chocolate or vanilla is expected to increase sensory 
acceptability even more and mask algae oil flavor.  
0.4% algae oil in 12 oz. of soymilk equates to approximately 700 mg of combined EPA and DHA 
(453 mg DHA and 249 mg EPA). In the 2020-2025 Dietary Guidelines for Americans, it was 
recommended to consume 8-12 oz of seafood per week, providing an average of 250-375 mg of 
the polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)8. 
The dietary guidelines cite the reduction in risk of cardiac deaths and beneficial effects for 
women who are pregnant or breastfeeding as the primary reasons for the seafood 
recommendation. Based on these recommendations, 700 mg of EPA and DHA should be more 
than enough per serving. However, many studies looking at the health benefits of EPA and DHA 
from fish or algae use servings of around 1 gram or higher 2,9. Therefore, multiple servings could 
be given depending on the goals of the clinical trial. 
This study will compare the algae oil fortified soymilk to a commercial algae oil capsule 
containing the same base oil with the goal of demonstrating equivalent or greater accumulation 
of EPA and DHA in blood lipid pools.  
III. Procedures 
A. Research Design 
This study will compare blood EPA and DHA concentrations over time after daily consumption 
of algae oil capsules or algae oil fortified soymilk. The proposed study is a randomized parallel 
arm trial involving 24 healthy participants. The study will be open label, since participants will 
know if they are consuming the study agent or pill. The intervention will include a 2-week 
placebo run-in phase and a 4-week intervention (Figure 1) with 4 total clinic visits to the OSU 
Clinical Research Center (CRC).  
 
Figure 1: Study Design 

Approval Date: 3/6/2023 
B. Sample 
This study will include healthy participants aged 18-60 years of age with a body mass index 
(BMI) between 18 and 30 kg/m2.  
Exclusion criteria will include: 
• 
Being pregnant or nursing 
• 
Having anemia or a condition that influences the ability to donate blood safely 
• 
Allergies to the beverage or pill ingredients 
• 
Diabetes 
• 
High triglycerides or cholesterol 
• 
Coagulation disorder 
• 
Anticoagulation therapy or any drug that affects blood clotting. 
o The NIH states that omega-3 supplements may interact with drugs that affect 
blood clotting (https://www.nccih.nih.gov/health/omega3-supplements-in-depth). 
• 
Taking prescribed dietary omega-3 fatty acid medications including fish oil or algae oil 
within the last 3 months 
• 
Taking non-prescribed dietary omega-3 fatty acid supplements within the last 3 months 
and not willing to discontinue taking them for the study period 
• 
Taking lipid lowering medications such as statins 
• 
Sensory impairments which affect ability to taste, smell, or see food products 
Sample size justification 
• 
The sample size (10 per group) was calculated based on a one way ANOVA with a 
meaningful mean difference of 20%, power of 0.80, alpha of 0.05, and a standard 
deviation of 15% based on literature values of erythrocyte DHA levels 6. The expected 
dropout rate is 20%. Therefore, 24 participants will be recruited.  
Recruitment strategy  
Informational flyers will be posted in various places across OSU’s campus including the Food 
Science and Technology building, Howlett Hall, and Campbell Hall. Additionally, an email will be 
sent to the student list services including the Food Science and Technology, OSU Nutrition, and 
Horticulture lists. The study may also be advertised in college and departmental newsletters if 
needed. Emails and flyers are attached. Interested subjects will be directed to a Qualtrics 
survey for pre-screening to determine eligibility. Those who meet the study criteria will be 
contacted by the study coordinator, Abigail Sommer, to begin the informed consent process.  
It is expected that subject accrual will be achieved using these methods as they have been 
successful previously in multiple of our sensory evaluation and clinical studies.  
Pre-Screening 
Interested participants will be screened through a Qualtrics survey to assess for inclusion and 
exclusion criteria defined in the previous sections. The Qualtrics survey is attached this 
application. Abigail Sommer will review the responses to determine if inclusion and exclusion 
criteria are met before contacting those eligible.  
Informed Consent  

Approval Date: 3/6/2023 
Persons who are interested and eligible will be scheduled for a Day -15 visit with a study 
coordinator at the CRC. On the first visit, participants will begin the informed consent process 
and all study procedures will be explained. If they agree to participate, subjects will be given a 
copy of the informed consent form for their records. 
C. Measurement and Instrumentation 
1. Biological Measures 
The EPA and DHA concentration in multiple blood fractions will be measured including 
erythrocytes, peripheral blood mononuclear cells (PBMC), platelets, and plasma.  
Erythrocyte fatty acids concentration correlates better with intake and reflect longer term intake 
as compared to plasma 10. Therefore, the primary objective is to determine if erythrocyte DHA 
and EPA levels differ after consuming algae oil fortified soymilk versus commercial algae oil 
capsules daily for four weeks.  
A total of 24 mL of blood will be collected at each time point into two Vacutainer EDTA tubes (6 
mL each) and 2 CPT tubes (8 mL each).  
Blood collected into EDTA tubes will be inverted immediately following collection and then 
stored on ice until centrifugation (within 1 hour of collection). EDTA tubes will be centrifuged at 
1932 x g for 10 minutes at 4°C. The plasma will be extracted and aliquoted into 2 mL tubes. 
Tubes will be stored on ice after aliquoting. The buffy coat layer will be removed and discarded, 
and the red blood cells will be extracted. The plasma and RBC aliquots will be stored at -80°C 
until analysis.  
Blood collected in the CPT tubes will be prepared according to the manufacturer’s instructions. 
The tubes will be stored upright and centrifuged within 2 hours of collection. The tubes will be 
inverted before centrifuging at 1800 x g for 30 minutes at room temperature. A portion of the 
plasma will be removed from the top of the tube and the cells will be resuspended in PBS buffer 
to a volume of 15 mL. The tube will be inverted to mix and centrifuged again at 300 x g for 15 
minutes. The cells will be washed again with PBS. The remaining pellet will be mixed with 1 mL 
of PBS and then transferred to 2 mL tubes. After centrifuging again at 300 x g for 5 minutes the 
supernatant will be aspirated off and the cell pellet will be stored at -80°C until analysis.  
Fasting blood samples at each time point will be collected into two Vacutainer tube containing 
EDTA and immediately stored on ice until centrifugation at 1932 x g for 10 min at 4C. Blood will 
also be collected in one CPT tube to be used for PBMC samples.  
Blood will be separated into three fractions, plasma, PBMC and erythrocytes using previously 
described methods1112. Plasma will be stored at -80°C until analysis. PBMC and erythrocytes 
will be washed with buffer and hemolyzed before being stored at -80°C until analysis.  
Fatty acid methyl esters in each fraction will then be separated and analyzed using gas 
chromatography as described previously12. Briefly, lipids from each fraction will be extracted 
with chloroform and methanol and methylated with hydrochloric acid in methanol. Erythrocyte 
fatty acids will be extracted and methylated using boron-trifluoride in methanol. Fatty acid 
methyl esters will then be analyzed using gas chromatography.  
Other lipid species and metabolites including cholesterol, eicosanoids, and hormones (leptin, 
adiponectin, and insulin) may be measured as exploratory endpoints. 

Approval Date: 3/6/2023 
2. Clinical and Anthropometric Measures 
Vital Signs 
Pulse, blood pressure, and temperature will be obtained by trained, registered nurses in the 
CRC using standard clinical methods.  
Body weight 
Participants will be weighted, wearing light clothing, on a standardized scale.  
Height 
Height will be measured using a standardized wall-mounted scale. 
Body mass index 
Body mass index will be calculated using the weight in kg divided by the square of height in 
meters. 
3. DHA and EPA Concentration in Ingredients, Beverages, and Capsules 
Although the certificates of analysis are provided for the Life’s Omega 60 algae oil and the algae 
oil capsules, we will verify the lipid profile of each to ensure standardization of the two agents.  
Fatty acid profiles of algae oil capsule, Life’s Omega 60 bulk algae oil (used in beverages), and 
fortified soymilk will be analyzed. A sterile needle will be used to extract oil from algae oil 
capsules. Oil from beverages will be extracted using chloroform and methanol. Fatty acids from 
each oil will be methylated and analyzed using gas chromatography as described previously12.   
4. Food Frequency Questionnaire 
To assess diet history, especially habitual consumption of fish and shellfish or fish oil 
supplements, as well as plant-based milk beverages, a validated food frequency questionnaire 
will be used.  
The Diet History Questionnaire III (DHQIII) from the NIH National Cancer Institute will be used 
(https://epi.grants.cancer.gov/dhq3/index.html). The study coordinators will create a study 
through the institute site to record and obtain data. The DHQIII includes information on 135 food 
and beverage items and 26 dietary supplements. The data will be collected for the past month 
with portion sizes.  
Responses will be collected from the participants online when convenient for them during the 
first week of the study. Login information will be provided at the first clinic visit. 
Data from the DHQIII may also be used to assess the Healthy Eating Index of each participant.  
5. Sensory Evaluation 
Sensory evaluation will be recorded during the first day of control beverage consumption for all 
panelists and during the first and last day of fortified beverage consumption for the algae oil 
beverage group only. Sensory evaluation will not be performed on the algae oil pills. 
The sensory evaluation will include acceptability, just about right, and descriptive attribute tests 
as well as general impressions. The acceptability tests will include a 9-point hedonic scale from 

Approval Date: 3/6/2023 
dislike extremely to like extremely. The categories measured will be overall liking, aroma 
(smell), flavor (taste), texture (mouthfeel), and appearance.  
The JAR tests will measure the level of serving size, chocolate aroma, chocolate flavor, 
sweetness, and thickness using 5-point scales from “much too little” to “much too much” of an 
attribute, with the middle being just about right.  
The descriptive attribute test will measure their opinion on the intensity of a specific attribute 
including fishy aroma/flavor, beany aroma/flavor, sweetness, chalkiness, viscosity, and 
astringency. The scale used will measure intensity from barely detectable to strongest 
imaginable using a validated labeled magnitude scale.  
Finally, there will be questions on general impressions including the sample size of beverages 
they would consume in a single day, the bottle size, and the flavor.   
6. Daily Intake and Symptom Journal 
A daily intake journal will be used to assess compliance. Subjects will record if and when they 
consumed the beverage or pill each day. Additionally, they will record If and when they 
consumed any of the restricted foods such as fish or shellfish and how much. The final part to 
the daily log will include recording symptoms such as bad breath, nausea, or bloating.  
D. Detailed Study Procedures 
Study Agent Information 
The study agent is a flavored soymilk beverage fortified with food grade algae oil (Life’s Omega 
60, DSM, Heerlen, Netherlands). The beverage has been validated by our lab to be physically 
and oxidatively stable over time and be acceptable in sensory evaluation studies.  
The control agent will be a commercial algae oil pill (Swanson Plant Based Omega-3) 
containing the same Life’s Omega 60 oil. These supplements are produced in an NSF 
International registered facility utilizing good manufacturing practices. Additionally, their purity 
and potency are assessed by an independent third-party laboratory. 
https://info.nsf.org/Certified/455GMP/Listings.asp?Company=C0054895&Standard=455-2GMP  
https://info.nsf.org/Certified/GMP/Listings.asp?Company=C0054895&Program=DIETSUPP  
All plant milk samples will be prepared in the FDA inspected Food Processing Pilot Plant 
(Howlett Hall) or the Dairy Processing Pilot Plant (Parker Food Science and Tech Building) 
using Good Manufacturing Practices. All products prepared for human consumption in this 
project contain wholesome food ingredients and Generally Recognized as Safe food additives. 
All ingredients will be food grade.  
Algae oil (0.4%) will be mixed with high oleic sunflower oil, liquid lecithin, and butylated hydroxy 
toluene (BHT) and stirred on a hot plate set to 500 rpm and 50°C until lecithin is evenly 
dispersed (about 10 minutes). The water phase will be prepared by mixing 0.1% gellan gum and 
1% polysorbate 80 into water using a hot plate set to 1000 rpm and 85°C. To prepare the base 
emulsions, 21%  
Concentrated soymilk base or soymilk powder will be combined with water (to manufacturer’s 
instructions) sugar (2%), salt (0.1%), emulsion base (10%), and cocoa powder (2-3%) before 

Approval Date: 3/6/2023 
being homogenized, and heat treated (136°C for 4 seconds). The plant milks will be cooled and 
bottled in aseptic hood. All samples will be refrigerated after bottling.  
Fresh soymilk will be prepared less than one week before the first week of the study and will be 
utilized throughout the duration of the study. Prior to this study, a confirmatory shelf-life study 
will be done to ensure that the storage time does not influence the fortified soymilk sensory 
perception. If needed, fresh samples can be prepared weekly or biweekly to ensure 
acceptability. 
First Clinic Visit 
Recruited subjects will meet with the study coordinator at the CRC to begin the informed 
consent process. The study coordinator, Abigail Sommer, will explain all study procedures as 
well as explain how to follow the low marine omega-3 diet, fill out daily intake and symptom 
logs, sensory evaluation forms, and the food frequency questionnaire.  
If the subject agrees to participate, they will be given control beverages to consume during the 
run-in phase and forms including sensory evaluation, food frequency questionnaire, and daily 
intake and symptom logs. Finally, a preliminary blood sample will be taken from the participant 
to assess their usual levels of EPA and DHA in blood lipid pools before the washout.  
Run-in Phase 
The study will include a 2-week placebo run-in phase where subjects will consume one serving 
of the control beverage per day with no algae oil. During the run-in the participants will complete 
a daily intake log, monitoring if and when they consumed the control beverage, as well as 
complete a log of symptoms, and sensory evaluation on the beverage. These tasks will help 
familiarize them to the procedures that will be performed during the rest of the study.  
Additionally, the two weeks will serve as a washout where they will be instructed to avoid a list 
of foods and supplements containing EPA and DHA. A food frequency questionnaire will also be 
used to assess usual intake of fish, shellfish, and plant-based milk beverages and healthy 
eating index.  
Participants will be asked if they would like to receive email reminders detailing daily tasks. If so, 
study coordinators will send emails reminding the subjects of each daily task including drinking 
the beverage or taking the pills, filling out the daily dairy and applicable DHQIII or sensory 
evaluation tasks. Additionally, each participant will be reminded of clinic visits and instructions to 
come having fasted for 12 hours.  
Study Phase 
After the run-in, the participants will then be randomized to the beverage or pill group. During 
the study phase, there will be three clinic visits to the Cancer Research Center. The visits will 
occur on day 0, 14, and 29. At each visit, blood will be drawn. 
Additionally on days 1 and 28, they will perform a sensory evaluation on the beverage using 
provided forms. The second sensory evaluation will be used to determine if long-term 
consumption of the beverage impacted its perception.  

Approval Date: 3/6/2023 
Over the course of the 28 days, participants will complete daily intake and symptom logs to 
ensure compliance to the low marine omega-3 diet and study intervention as well as monitor 
adverse effects.  
To ensure compliance during the study, participants will be asked to return empty beverage or 
pill containers and any that were not consumed. One to three extra beverages or pills will be 
given to estimate how many were consumed.  
Participants will again be asked if they would like to receive email reminders detailing daily 
tasks.  
Low Marine Omega-3 Diet 
Subjects will be instructed to follow a diet low in marine omega-3s including EPA and DHA. This 
diet will restrict the following items: fish (salmon, anchovies, swordfish, halibut, tuna, trout, 
sardines, cod, pollock, catfish, mahi mahi, etc.), shellfish (mussels, oysters, crab, scallops, 
shrimp, clams, lobster, etc.) and EPA and/or DHA enriched foods, or supplements containing 
fish or algae oils. If the participant does accidentally consume a restricted food, they will be 
asked to record the date, time, and amount of food item.  
Risks and Benefits  
A medical doctor, Dr. Steven Clinton, will be notified immediately of any adverse events and the 
study coordinator will report any serious adverse events to the OSU IRB and the OSU clinical 
scientific review committee. 
The risk of consuming omega-3 fatty acids in the form of algae oil are extremely low. Omega-3 
supplements usually produce only milk side effects such as unpleasant taste, bad breath, bad-
smelling sweat, headache, and gastrointestinal symptoms such as heartburn, nausea, and 
diarrhea13. Up to 5 g of EPA and DHA supplements has been concluded to be safe by the Food 
and Drug Administration13. This study utilizes a dose well under 5 g and additional sources of 
EPA and DHA should be minimized in the diet due to the restrictions of the study.  
Omega-3 dietary supplements can interact with certain medications including blood thinners and 
anticoagulants such as Warfarin13. During the screening process, those taking these 
medications will be screened out and not allowed to participate in the study, minimizing this risk.  
We will assess each patient for any adverse event using the Common Terminology Criteria for 
Adverse Events (version 4.0) from the National Cancer Institute and National Institutes of 
Health. Patients who develop a grade two adverse event will be asked to stop the intervention. 
Although unexpected with a food product, if we see 2 similar grade three adverse events, we 
will stop the study and ask all men and women to discontinue the intervention. 
The likelihood of serious adverse events is very low.  The compounds in the foods provided are 
commonly found in a general, varied diet. However, any life-threatening reactions, which may 
be due to the beverage or supplement and all fatal events while on study or within 30 days of 
treatment, and the first occurrence of any previously unknown toxicity of any grade will be 
reported as serious adverse events. The Study Coordinator or data manager will report these 
reactions within 24 hours to the National Cancer Institute Investigational Drug Branch and the 
IRB within 10 working days. The principal investigator and the attending physician in 
collaboration with the NCI, if necessary, will decide if a toxicity is most likely drug related. 

Approval Date: 3/6/2023 
The benefits to the participant’s health over a short period of time are unknown and likely to be 
small. In order to compensate participants for time and effort as well as parking and travel costs, 
we will provide $20 in cash for the first three clinic visits and $40 in cash for the final clinic visit 
and $16 in cash, $4 per visits, as reimbursement for one hour of parking in the Wexner Medical 
Center Garage or Davis Outpatient Garage.parking passes as needed.   
Subject confidentiality 
Strict patient confidentiality of records will be maintained.  Random 2-digit numbers will be 
assigned to each subject and will be used to identify all of that subject’s samples and files. 
Individuals will not be identified by name or by any other personal identifying information in 
laboratory records, reports, or publications resulting from this study. Thus, risk of disclosure of 
confidential medical information will be essentially nonexistent. The project team has 
procedures in place to maintain confidentiality, such as password protected computer access, 
locked file cabinets and rooms where records are stored, and all team members have received 
appropriate training, in full compliance with HIPAA. Only the Investigators and study 
coordinators will have access to any subject data. 
Personal data will be kept at least until publication of results, but in most cases is kept longer in 
case potential follow up studies with the same subject will be designed. Typically, personal 
information will be shredded after 10 years, and all computer files carrying personal identifying 
data will be erased.  
Limitations and Potential Pitfalls 
The capsules will utilize the same oil product (Life’s Omega 60 oil, DSM) but will not contain the 
exact same lot. To standardize the oil as much as possible, the EPA and DHA content of the 
pills and beverage will be measured, with the oil concentration of the beverage being adjusted 
to match that of the pill if possible.  
Internal and External Validity 
Subjects will be stratified by gender and randomized to the study arms to enhance study internal 
validity. Age, BMI, and initial EPA and DHA levels will be measured in all participants to ensure 
even distribution across study arms. If differences in these variables are found, they will be used 
as covariates in data modeling.  
Efforts will be made to ensure a diverse sample of study participants by recruiting from various 
areas around campus and not just recruiting students. Women will represent 50% of the study 
participants. No participant will be excluded on the basis of race or ethnicity.  
Data Analysis 
All data analysis will be performed using SAS statistical software.  
The impact of the algae oil form on the primary outcome of change in erythrocyte EPA and DHA 
concentration will be evaluated using analysis of variance (ANOVA). Covariates including BMI, 
height, weight, sex, age, ethnicity, and pre-trial and baseline levels of EPA and DHA will be 
evaluated using a forward selection procedure.  
The influence of product type on secondary outcomes including EPA and DHA concentrations in 
other blood lipid pools will also be evaluated using ANOVA.  

Approval Date: 3/6/2023 
Compliance will be measured using the daily intake log and number of empty bottles, pills 
received at each clinic visit. The number of days that the beverage is consumed and any 
noncompliance with the marine omega-3 restricted diet divided by the number of total days will 
be used to report compliance.  
Exploratory analyses including influence of algae oil vehicle on various blood lipids, hormones, 
and metabolites and the influence of diet on various variables may also be performed.  
IV. References 
1. 
Ellulu, M. S. et al. Role of fish oil in human health and possible mechanism to reduce the 
inflammation. Inflammopharmacology 23, 79–89 (2015). 
2. 
Kris-Etherton, P. M., Grieger, J. A. & Etherton, T. D. Dietary reference intakes for DHA 
and EPA. Prostaglandins Leukot. Essent. Fat. Acids 81, 99–104 (2009). 
3. 
Doughman, S., Krupanidhi, S. & Sanjeevi, C. B. DHA-Rich Algae Oil Is a Safe and 
Effective Vegetarian Source of Omega-3. in Omega-3 Fatty Acids: Keys to Nutritional 
Health (eds. Hegde, M. V., Zanwar, A. A. & Adekar, S. P.) 263–266 (Springer 
International Publishing, 2016). doi:10.1007/978-3-319-40458-5. 
4. 
Puranik, S. S. Emulsions of Omega-3 Fatty Acids for Better Bioavailability and Beneficial 
Health Effects. in Omega-3 Fatty Acids: Keys to Nutritional Health (eds. Hegde, M. V., 
Zanwar, A. A. & Adekar, S. P.) 127–139 (Springer International Publishing, 2016). 
5. 
Hinriksdottir, H. H., Jonsdottir, V. L., Sveinsdottir, K., Martinsdottir, E. & Ramel, A. 
Bioavailability of long-chain n-3 fatty acids from enriched meals and from 
microencapsulated powder. Eur. J. Clin. Nutr. 69, 344–348 (2015). 
6. 
Wallace, J. M. W. et al. Bioavailability of n-3 polyunsaturated fatty acids (PUFA) in foods 
enriched with microencapsulated fish oil. Ann. Nutr. Metab. 44, 157–162 (2000). 
7. 
Arterburn, L. M. et al. Bioequivalence of Docosahexaenoic Acid from Different Algal Oils 
in Capsules and in a DHA-Fortified Food. Lipids 42, 1011–1024 (2007). 
8. 
U.S. Department of Agriculture & U.S. Department of Health and Human Services. 
Dietary guidelines for Americans, 2020-2025. (2020). doi:10.1001/jama.2016.0077. 
9. 
Ghasemi Fard, S., Wang, F., Sinclair, A. J., Elliott, G. & Turchini, G. M. How does high 
DHA fish oil affect health? A systematic review of evidence. Crit. Rev. Food Sci. Nutr. 59, 
1684–1727 (2019). 
10. 
Angelotti, A., Cole, R. M., Schnell, P. M., Raatz, S. K. & Belury, M. A. Evaluation of a 
Rapid Assessment Questionnaire Using a Biomarker for Dietary Intake of n-3 Fatty Acids. 
Lipids 54, 321–328 (2019). 
11. 
Vidgren, H. M. et al. Incorporation of n-3 Fatty Acids into Plasma Lipid Fractions , and 
Erythrocyte Membranes and Platelets During Dietary Supplementation with Fish , Fish Oil 
, and Docosahexaenoic Acid-Rich Oil Among Healthy Young Men. Lipids 32, 697–705 
(1997). 
12. 
Cole, R. M., Angelotti, A., Sparagna, G. C., Ni, A. & Belury, M. A. Linoleic Acid-Rich Oil 
Alters Circulating Cardiolipin Species and Fatty Acid Composition in Adults: A 
Randomized Controlled Trial. Mol. Nutr. Food Res. 66, 1–9 (2022). 
13. 
National Institutes of Health Office of Dietary Supplements. Omega-3 Fatty Acids Fact 

Approval Date: 3/6/2023 
Sheet for Health Professionals. https://ods.od.nih.gov/factsheets/Omega3FattyAcids-
HealthProfessional/ (2022).