Introduction: FDA has already taken some foods off the market.
On Wednesday September 25th, FDA’s Center for Food Safety and Applied Nutrition (CFSAN) held a public meeting discussing their proposed pathway for post-market assessment of chemicals in food.
FDA’s goal is to “provide more insight on the status of the FDA’s post-market assessments of chemicals in the food supply”. This assessment includes evaluation of previously approved and/or historically used food additives, color additives, generally recognized as safe (GRAS) substances and substances used in contact with food, as well as the presence of adventitious contaminants previously deemed harmless in the concentrations present in the diet. FDA has already taken some limited actions by revoking the generally recognized as safe (GRAS) status for partially hydrogenated oils (PHOs) containing trans-fats in 2015 and brominated vegetable oil (BVO) in July of 2024. California banned propylparaben, potassium bromates, and BVO in October of 2023.
Why this re-examination? New data and new uses for food ingredients
These post-market reevaluations of ingredients that had previously met the “reasonable certainty of no harm under the intended conditions of use” safety standard for food ingredients, are tangible steps towards food safety improvement. FDA’s current proposal is to react to newly released scientific data and take that into consideration with the already established body of scientific evidence available. However, it remains to be seen how FDA will review the vast compendium of chemicals present in the food industry, what factors they will use to make such decisions, and how they will differ from the criteria they had used in the past to make safety determinations. For example, in the SCOGS[1] review of GRAS substances in the early to mid-1970’s many chemicals were determined safe based on limited scientific evidence and on use levels that may be substantially different than what is used today. Moreover, the inclusion of many ingredients from 21 Code of Federal Regulations (CFR) 182 and 184 were based on the lack of adverse effects being reported from safety studies that were conducted before the establishment of the Final Rule on GLP in June 1979.
Another point to consider is the fact a majority of safety studies conducted in the 1970s were oral studies; however, non-oral exposure to food ingredients can result in unique and sometimes detrimental effects. For example, inhalation of butter flavor ingredient, diacetyl, is known to induce bronchiolitis obliterans and Vitamin E acetate, which is often used in skin creams and also as a condensing agent for vaping products, can lead to E-cigarette or Vaping Product Use–associated Lung Injury (EVALI). Therefore, a post-market assessment will need to use a proactive approach to evaluate these and other chemicals added to food, based on a comprehensive toxicological review of past and current scientific data and an estimation of the aggregate exposure to these chemicals in all food and products via all potential exposure routes (e.g., as dietary supplements, cosmetics (i.e., breath mints, mouth wash, toothpaste), vapes, tobacco products, drugs (as excipients), aroma therapy and others.
Which chemicals to examine?
The first question is how such a post-market assessment should be conducted? FDA has proposed a review process that includes signal monitoring, triage, and a fit for purpose decision[2]. Food chemical signal monitoring entails identifying new information through multiple sources, including scientific publications, international and U.S. regulatory activities, adverse event reports, news reports and trade press, and social media. FDA would then conduct a preliminary quality and impact assessment, which would then ultimately be followed by either a focused or a comprehensive assessment of the chemical.
What makes the difference between a focused vs. comprehensive review? There are multiple factors FDA may consider for this, including the requirement for resources outside the purview of the Office of the Post -Market Assessment, the presence of a strong weight of evidence and scientific consensus about the potential significant impact on the original conclusion of the reasonable certainty of no harm, concern from multilateral organizations or the public for safety, and of course, whether there are changes in dietary exposure that impact consumer health. Focused reviews would include new information available to determine if there is a safety concern and if so, do the levels of chemical currently in food exceed the reasonable certainty of no harm standard. FDA subject matter experts will determine whether action is necessary to protect public health and outline possible mitigation strategies and associated benefits to public health. FDA will communicate its decision and take any appropriate risk management actions, which may include possibly being referred for prioritization as part of a Comprehensive Assessment. However, FDA will have to remain pragmatic when using this process to prevent endless rounds of review that would result in little to nothing being accomplished.
FDA’s justification for examining a chemical
Therefore, to avoid wasting time and FDA’s resources on potentially hyperbolic and nugatory claims surrounding the alleged dangers of a substance, FDA must be more circumspect in evaluating evidence, including what chemicals they examine and the sources they use to evaluate those chemicals. FDA has stated they would consider social media as an information resource; however, social media is unfiltered and there is no way to qualify the information provided nor the source of the information on a chemical. Complaints could be based on incomplete information or launched by individuals who are not qualified to make toxicity claims, leading to hysteria. For example, during the 1959 Thanksgiving cranberry scare, the Secretary of Health Education and Welfare, Arthur Fleming, announced that cranberry products were contaminated with the herbicide, aminotriazole,[3] which had been shown to cause cancer in the thyroid of rats. This almost destroyed the cranberry industry and cost millions of dollars. The concentration found in cranberries did not warrant a concern for carcinogenicity but could not be in food since the passing of the 1958 Food Additives Amendment and the Delaney Clause.[4] Since then, detection methodologies have determined many foods have known carcinogens, which include pesticide chemicals. The Food Quality Protection Act (FQPA) of 1996 was passed, which permitted the presence of contaminants (such as a pesticide chemical) in food, as long they were within the tolerance levels, which were established by EPA for that particular contaminant and food group. As a result, the FDA has made the determination that for carcinogenic contaminants, the manufacturer has to show that:
· The manufacturing process was such that the contaminant had been reduced to the lowest possible level
· The contaminant could be exempted if it was present in an amount that was (a) less than the median toxic dose (TD50) in published carcinogenicity studies or (b) the carcinogen was in the diet at or below 0.5 ppb (based on a diet of 3 kg/day).[5]
However, in 1960, even though it was acknowledged aminotriazole was goitrogenic and caused tumors in rats, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) concluded, “there does not appear to be any evidence that they give rise to tumors in man”.[6]
In 1990, the plant growth regulator, daminozide,[7] was associated with the Alar apple scare, which was an environmental and public health canard motivated by politics rather than concrete science. Although in 1985 the Environmental Protection Agency (EPA) concluded Alar was a probable human carcinogen, it was later concluded by the Scientific Advisory Panel (SAP) there was inadequate information to determine the carcinogenicity of the substance. Nonetheless, a majority of the SAP members were accused of having a “pro-industry bias”, leading to the American Academy of Pediatrics urging EPA to ban the chemical and supermarkets refusing to sell apples that had Alar. Furthermore, a two-year peer-reviewed study by the NDRC[8] led to a conclusion that EPA-permissible levels of Alar posed an “intolerable risk” to children.[9] Ultimately EPA banned the substance; however, epidemiologist Elizabeth Whelan from the American Council on Science and Health (ACSH) concluded that Alar and its metabolite UDMH had not been shown to be carcinogenic and that the NDRC ignored the rudimentary precept of toxicology (i.e., the dose makes the poison).[10]
In a 2002 Swedish study, acrylamide, which is used in wastewater treatment and a potential neurological and developmental toxin and carcinogen, was found in many starchy foods including potatoes, French fries, breads, and cereals. Activists in the media claimed that starchy foods (including fries, cereals and potato chips) had up to 100-500 times the acrylamide that was permitted by the World Health Organization (WHO) regulations and could pose a cancer risk. This led to Proposition 65 (Prop 65) enforcement via the California Attorney General’s office by the Council for Education and Research on Toxics (CERT) against McDonald’s, Burger King, and other fast-food restaurants and grocery store brands for failure to warn consumers about acrylamide in French fries and other starchy snacks. However, a research article in the British Journal of Cancer[11] and two epidemiological studies[12],[13] published in the International Journal of Cancer concluded there was no association between dietary acrylamide consumption and cancer risk. Although FDA has stated they do not know the exact risk acrylamide poses to humans, they have also admitted that there is no consistent epidemiological evidence on the effect of acrylamide from food consumption on cancer in humans.[14] Despite the fact acrylamide has been shown to cause cancer at very large doses in animals, as of the date of this newsletter, there is no evidence that the levels of acrylamide consumed in the daily diet pose such a risk to humans.
Many papers that are published also get retracted, and this is due to many factors including poor data, plagiarism and/or fabrication of data, and papers written by artificial intelligence (AI). A review paper reported that various food additives, including sweeteners like aspartame and preservatives like sodium and potassium benzoate, had multiple toxicological and teratogenic effects;[15] however, it was later retracted after an investigation revealed multiple indicators of “systemic manipulation”. A cancer researcher at University of Texas MD Anderson, Bharat Aggarwal, had at least 29 papers retracted which focused on the chemotherapeutic/chemopreventive properties of herbs and spices (in particular curcumin), based on fabricated images and falsified results.[16],[17],[18] Another retracted study claimed that long term exposure to genetically modified corn and the herbicide roundup, which contains glyphosate[19], increased the likelihood of chronic diseases such as cancer and kidney and liver issues. Although there were no concerns of fraud, the strain and number of animals used in study led to concern over the validity of the conclusion that glyphosate had any impact on tumor incidence or mortality. At one point there were concerns that glyphosate was an endocrine disruptor and/or carcinogenic,[20] being associated with non-Hodgkin lymphoma; however, a myriad of regulatory agencies and scientific organizations, including the EPA, the Joint FAO/WHO Meeting on Pesticide Residues (JMPR), the European Commission, and the Canadian Pest Management Regulatory Agency concluded glyphosate is unlikely to have any carcinogenic potential. Overall, these select examples demonstrate that FDA must show discretion and restraint when utilizing its resources to justify unnecessary investigations into chemicals, which can lead to wastes of time and money.
Therefore, to determine whether a chemical poses a significant safety issue in the food chain requires experts qualified by scientific training and experience. To establish the safety in use of a chemical, the following must be addressed: the proposed use, a detailed manufacturing process, compositional and specification analyses, and safety via dispositive evidence in testing, including in vivo and in vitro toxicity testing, genotoxicity and allergenicity testing. Burdock Group has great experience in reviewing and collecting scientific literature relevant to the safety of the substance, with access to conduct comprehensive literature searches on chemicals using Scopus® database, a product of the Elsevier publishing company, the largest and most comprehensive scientific database available. Burdock Group also uses author informative databases such as the European Chemicals Agency (ECHA) and SEARCH, and international publications published by the European Food Safety Authority (EFSA) and JECFA. We can evaluate the quality of these studies, determining whether they were conducted according to GLP and Organization of Economic and Cooperative development (OECD) guidelines and/or if they have been assigned a reliability score based on Klimisch criteria.
Determining exposure to a chemical – as an added ingredient and via natural exposure.
So, what methods should be used to estimate the aggregate exposure of these chemicals in food and other products? Originally in the 1970’s, FDA revised the list of approved food ingredients based on the results of confidential surveys from manufacturers, and in collaboration with the National Academy of Sciences. Based on this information, FDA was able to gain insight into changes in volume of various ingredients, indicating additional and perhaps unapproved uses of the ingredient but most important, an estimate of the mean and 90th percentile per capita intake.
Burdock Group utilizes proprietary software to predict the mean and 90th percentile level of consumption of a chemical from particular foods, which considers the demographics, sex, age, and respective eating habits of the consumers. This data is based on the food intake profile of individuals provided by the United States Department of Agriculture (USDA)’s What We Eat in America (WWEIA) based on food categories. WWEIA Food Categories are intended for use with dietary intake data the National Health and Nutrition Examination Survey (NHANES) and the USDA Food and Nutrient Database for Dietary Studies (FNDDS). With this proprietary software, we can calculate how much substance consumers will be exposed as the result of the addition of a substance to a food, based on the concentration of the substance that is added to a food group and how many eaters consume that particular food groups. As part of the aggregate exposure to a substance, information can also be derived from the suggested daily intake provided on the label of a dietary supplement, to which then is added amount of the substance which occurs naturally in plants (the amount of plant, herb or spice can also be determined in WWEIA) of the substance is included, yielding an estimation of the level of daily oral exposure from multiple sources for the substance. This aggregate intake would then be compared to the Acceptable Daily Intake (ADI), which is a measure of the amount of the substance that can be consumed in food over time without any appreciable health risks. The ADI is based on a Margin of Exposure (MOE) (i.e., safety factor) between the 90th percentile level of consumption of a substance and the most conservative No Observed Adverse Effect Level (NOAEL) from a 90-day OECD-compliant rat study. FDA usually requires a 100-fold MOE to take into consideration interspecies (difference from rat to man) and intraspecies (differences between individual rats) variation.[21]
Conclusion
To conclude, a post market assessment is a commendable action to take to make the food supply safer for the general public. FDA has provided a plausible path forward to audit the current food and product supply. However, this approach needs to have an overarching approach that not only reacts to safety information published, but also critically evaluates the data and safety determinations for chemicals that are currently in food to determine if the reasonable safety threshold is met. FDA must also exercise discretion when evaluating the alleged toxicological impact of a chemical in relation to the quality of evidence provided, the source providing the evidence, and how this evidence relates to the aggregate exposure to that chemical in the food supply. Moreover, FDA may lack the training, expertise, and number of personnel required to address this task. Burdock Group has the qualifications and the resources to provide real answers to real questions in real time, without the delays and bureaucratic red tape that has previously hindered the response to public safety when it comes to the food and product supply.
About the Author
Dr. Hedrick received his Ph.D. in Toxicology in 2016 from Texas A&M University and has seven years of post-doctoral experience from Texas A&M University and the Lerner Research Institute of the Cleveland Clinic. With ten years of toxicology experience relating to molecular toxicology and over fourteen years of experience in cell/molecular biology, biochemistry, and molecular oncology, Erik has acquired extensive experience utilizing in vitro and in vivo molecular, biochemical, and analytical techniques as well as animal husbandry in the field of molecular toxicology and oncology.
He has published 21 peer-reviewed publications in multiple highly respected journals. During this time, Erik has successfully obtained highly competitive sources of funding for research, including a Merit Scholars Fellowship and Research Training Grant at Texas A&M University, the National Institute of Health (NIH) Ruth L. Kirschstein National Research Service Award (NRSA), and the Early Investigator Research Award during his postdoctoral tenure at Cleveland Clinic. Erik has presented his work at multiple scientific conferences, including the Society of Toxicology (SOT) annual meetings.
As the Director of Toxicology here at Burdock Group, Erik’s role is to ensure the safety and regulatory compliance of a client’s product before it comes to market. His experience in toxicology has equipped him with the toolset to understand the unique safety requirements for an ingredient and what tests are needed to demonstrate safety. During Erik’s tenure at Burdock Group, he has become familiar with specific regulations within the United States and the European Union. This includes working with the Food and Drug Administration (FDA) and the Environmental Protection Agency (EPA) within the United States, as well as with the European Food Safety Authority (EFSA) within the European Union (EU).
[1] The acronym for Select Committee of GRAS Substances, an independent panel of experts selected by the Federation of American Societies for Experimental Biology.
[2] The FDA will decide whether to conduct a Focused or Comprehensive Assessment, which will be contingent on the likely complexity of the assessment needed, considering a number of factors described below.
[3] Ross, G. (2015) The 1st Great Chemical Cancer Scare? Cranberries, Thanksgiving 1959. American Council on Science and Health. https://www.acsh.org/news/2015/11/23/the-first-great-chemical-cancer-scare-cranberries-thanksgiving-1959; site visited October 17th, 2024.
[4] Banned the addition of substances known to be carcinogenic to food.
[5] Based on the Threshold of regulation for substances used in food-contact articles; https://www.ecfr.gov/current/title-21/chapter-I/subchapter-B/part-170/subpart-B/section-170.39; site visited October 17th, 2024
[6] Joint FAO/WHO Expert Committee on Food Additives (1960) “Evaluation of the Carcinogenic Hazards of Food Additives” Fifth Report of the Joint FAO/WHO Expert Committee on Food Additives. Owrld Health Organization Technical Report Series. No. 220.
[7] More commonly known as Alar.
[8] National Research Defense Council
[9] Marshall, E. (1989). "Science Advisers Need Advice [News & Comment: Ethics in Science]". Science. 245 (4913). American Association for the Advancement of Science: 20–22. doi:10.1126/science.2740907. PMID 2740907. Retrieved 13 August 2022. Charges that two scientists who served on an EPA advisory panel later broke conflict-of-interest laws raise some vexing questions; site visited October 17th, 2024
[10] Whelen, E. (1991). "Cancer Scares and Our Inverted Health Priorities". Imprimis. 20 (6); https://imprimis.hillsdale.edu/wp-content/uploads/2016/11/Cancer-Scares-And-Our-Inverted-Health-Priorities-June-1991.pdf; site visited October 17th, 2024
[11] Mucci, L.A.; Dickman, P. W.; Steineck, G.; Adami, H-O.; Augustsson, K. (2003) Dietary acrylamide and cancer of the large bowel, kidney, and bladder: absence of an association in a population-based study in Sweden. British Journal of Cancer. 88(1):84-89.
[12] Mucci, L. A.; Lindblad, P.; Steinbeck, G.; Adami, H-O. (2004) Dietary acrylamide and risk of renal cell cancer. International Journal of Cancer. 109(5):774-776
[13] Pelucchi, C.; Franceschi, S.; Levi, F.; Trichopoulos, D.; Bosetti, C.; Negri, E.; Vecchia, C.L. (2003) Fried potatoes and human cancer. International Journal of Cancer. 105(4):558-560
[14] https://www.fda.gov/food/process-contaminants-food/acrylamide; site visited October 21st, 2024.
[15] Sambu, S.; Hemaram, U.; Murugan, R.; Alsofi, A. (2022) Toxicological and Teratogenic Effect of Various Food Additives: An Updated Review. Biomed Research International. 6829409.
[16] "The Retraction Watch Leaderboard". Retraction Watch. 16 June 2015. https://retractionwatch.com/the-retraction-watch-leaderboard/; site visited October 22nd, 2024
[17] Ackerman, T. (2012). "M.D. Anderson professor under fraud probe". Houston Chronicle. https://www.chron.com/news/houston-texas/article/m-d-anderson-professor-under-fraud-probe-3360037.php; site visited October 22nd, 2024.
[18] Caught Our Notice: Researcher who once threatened to sue Retraction Watch now up to 19 retractions". Retraction Watch. (2018). https://retractionwatch.com/2018/04/10/caught-our-notice-researcher-who-once-threatened-to-sue-retraction-watch-now-up-to-19-retractions/#more-63985; site visited October 22nd, 2024.
[19] A broad-spectrum organophosphate based herbicide that inhibits the enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSP).
[20] The International Agency of Research on Cancer (IARC) classified glyphosate as “probably carcinogenic to humans” in 2015.
[21] Both interspecies and intraspecies variation use a factor of 10; 10 x 10 = 100-fold.
Burdock Group Consultants stands as a premier authority in food safety and regulatory compliance, delivering customized solutions across various industries. Boasting over 35 years of experience as a frontrunner in regulatory and scientific consulting, our physical presence in Orlando enables us to offer clients direct accountability and access to cutting-edge scientific databases. These resources contain the latest and most thorough information necessary to determine the steps required to introduce your product into the market.
