You may have a blockbuster food or dietary supplement ingredient, but if the manufacturing process introduces contaminants, it may not be safe to consume. Contaminants may be introduced into a botanical ingredient during growth, such as heavy metals or herbicides from soil or pesticides or antifungal agents applied to plants. Toxins can be produced by plants or be introduced into plants during storage by fungal contamination. Ingredients that are produced by chemical synthesis may be contaminated with solvents or unintended metabolites, and ingredients that are manufactured by microbial fermentation can be contaminated with the microbes or toxins produced by them. Other sources of contaminants include water, processing aids, filters/columns, fermentation media ingredients and packaging materials. Use of Good Manufacturing Practice (GMP), potable water and food grade materials (by U.S. standards) can help reduce levels of contaminants in an ingredient. However, even if these procedures are in place, contaminants may be present in your ingredient.

Regulatory Standards for Limiting Potentially Harmful Contaminants in Food Ingredients

For food ingredients, potentially harmful contaminants are addressed by limiting the amount present in the specifications - higher than allowed amounts render the ingredient and the food to which it has been added, adulterated (see 21 US Code § 342). Common contaminants of ingredients include heavy metals and microbes, regardless of how they are produced. Therefore, specifications for ingredients typically include limits for heavy metals (lead, arsenic, mercury and cadmium), bacteria (i.e. total aerobes, E. coli and Salmonella) and yeast/mold. Specifications for other contaminants are added on a case-by case basis, depending on the source or type of the ingredient, method of manufacture and foods to which the ingredient is added. Ingredients that will be added to infant formula cannot be contaminated with Cronobacter sakazakii.

THE FDA'S APPROACH TO HEAVY METALS

Over the past 10-15 years, the FDA has been active in issuing guidance documents for intake of heavy metals (particularly lead) from food. This activity aligns with their Closer-to-Zero initiative for reducing childhood exposure to contaminants from food¹. Lead exposure is particularly hazardous for the fetus, infants and children because they absorb more lead from food than adults and are susceptible to the deleterious effects of lead on the developing nervous system². Exposure to high levels of lead has been associated with a reduction in intelligence quotient (IQ) and adverse effects on behavior. The Centers for Disease Control and Prevention (CDC) has been monitoring blood lead levels (BLL) of children who are at risk for lead poisoning for decades and has steadily reduced the blood lead level (BLL) health care providers should use for identifying children who need intervention to reduce lead exposure.

ALIGNING THE FDA AND CDC POLICIES: EVOLUTION OF LEAD ACTION LEVELS AND RECOMMENDATIONS

In 2012, the CDC changed its BLL recommendation from 10 µg/dL to 5 µg/dL and in 2021, the CDC further reduced it to 3.5 µg/dL³. Since the early 1990s, the FDA has aligned their lead policy with that of the CDC. In 1992, the FDA used the CDC’s benchmark of a 10 µg/dL BLL to develop provisional tolerable total daily intakes for lead of 6 μg/day for young children and 25 μg/day for pregnant or lactating women⁴. As the CDC has steadily dropped their lead action levels, so has the FDA. However, to account for sensitive individuals, the FDA has applied an additional safety factor of 10 to the CDC’s recommendations. In 2020, based on the reduction in the CDC’s action level from 10 µg/dL to 5 µg/dL, the FDA developed interim reference levels (IRLs) for lead intake of 3 μg/day in children and 12.5 μg/ day in women of childbearing age and adults, which correspond to a BLL of 0.5 μg/day^5,2. In response to the CDC lowering their recommended BLL from 5 µg/dL to 3.5 µg/dL in 2021, the FDA further decreased the IRLs for lead to 2.2 μg/day in children and 8.8 μg/day in women of childbearing age, which correspond to a BLL of 0.35 μg/dL. This BLL corresponds to an IQ loss of < 1 point³.

THE FDA'S INITIATIVES TO MITIGATE LEAD EXPOSURE IN CHILDREN AND FOOD PRODUCTS

Other steps the FDA has taken to reduce lead exposure in young children include recalls for foods containing unsafe levels of lead and issuance of guidance documents for action levels for lead in baby food, juice and candy⁶. Because the FDA has lowered their guidance level for lead intake in children from 6 μg/day to 2.2 μg/day over the course of 30 years, it is evident that levels of lead that were permitted in food ingredients 30 years ago would not be permitted today. Because lead can be introduced into a product from raw materials, it is important for manufacturers to use raw materials that contain low levels of lead.

THE FDA'S NEW OPINIONS ON CADMIUM AND ARSENIC

Although the FDA has not been as active in developing guidance for exposure to heavy metals other than lead, recently they have issued a few opinions about action levels for cadmium and arsenic. In 2023, the FDA developed an oral toxicological reference value (TRV) for cadmium of 0.21–0.36 μg/kg bw/day⁷. Notably, the FDA hasn’t issued any guidance for cadmium prior to this publication, other than a limit of 5 ppb in bottled water. Recognizing that bottled water, apple juice and rice commonly contain inorganic arsenic (iAs), the FDA has issued a rule for a limit of 10 ppb iAs in bottled water and guidance for action levels of 10 ppb iAs in apple juice and 100 ppb iAs in infant rice cereal⁸. According to the FDA’s Closer-to-Zero Website, draft guidance documents for arsenic and cadmium in foods intended for babies and young children are expected in December, 2024¹. The FDA has not issued guidance for mercury other than advice for eating fish, which can contain methyl mercury⁹.

REGULATING MICROBIAL CONTAMINANTS IN FOOD INGREDIENTS

Microbes are different from other contaminants in that it is difficult to place a number on a safe versus an unsafe level of a microbe in an ingredient due to lack of animal or human studies that examine dose-response relationships. It is recognized that most, if not all food ingredients will be contaminated by aerobic bacteria and yeast/mold because these microbes are everywhere, but they should not contain bacteria that are known pathogens. Use of GMP, potable water, food grade materials (by US Standards), sterile media and frequent disinfection of equipment can help reduce bacterial contamination. Stability tests should include bacterial analyses because it is possible that microbial contamination will increase during storage, particularly if the contaminant is a spore-former.

ENSURING COMPLIANCE AND SAFETY IN FOOD INGREDIENT MANUFACTURING

Food ingredient manufacturers know that the FDA is serious when it comes to adulterated food. With the globalization of the food supply, there is increased risk of adulteration of food ingredients, especially when requirements from other countries may not be as stringent as the United States. Even if a manufacturing process reliably produces a food ingredient that is not adulterated, situations may arise which lead to contaminated or out of specification lots.

The GRAS Associates team offers a number of services regarding contaminants, including, but not limited to specification development, product contamination, and recall assistance. Don’t let contaminants get in the way of a blockbuster – give us a call.

About Dr. Dolan

With over 30 years of experience as a toxicologist, Dolan is responsible for scientific research and generation of safety dossiers related to GRAS, NDIN and risk assessments at GRAS Associates, a SGS Nutrasource Company.

Dolan is a Diplomate of the American Board of Toxicology (DABT), Fellow of the American College of Nutrition (FACN) and a past president of the Food Safety Specialty Section of the Society of Toxicology (SOT), bringing a wealth of knowledge and skill to the GRAS Associates team.

Prior to joining SGS Nutrasource, Dolan was most recently employed as a Senior Toxicologist in the Contaminant Assessment Branch at the FDA Center for Food Safety and Nutrition, where she routinely performed risk assessments for metal, toxin, chemical and pesticide contaminants. Dolan also has experience working as a consulting toxicologist, and a toxicologist for Procter and Gamble. She received her Bachelor of Science in Chemistry from SUNY Oswego before completing her PhD in Pharmacology/Toxicology at Michigan State University.

References

1. FDA (2024a). Closer to Zero: Reducing Childhood Exposure to Contaminants from Foods. Available at: https://www.fda.gov/food/environmental-contaminants-food/closer-zero-reducing-childhood-exposure-contaminants-foods.
2. Flannery, B. M., Dolan, L. C., Hoffman-Pennesi, D., Gavelek, A., Jones, O. E., Kanwal, R., Wolpert, B., Gensheimer, K., Dennis, S. and Fitzpatrick, S. (2020). US Food & Drug Administration's interim reference levels for dietary lead exposure in children and women of childbearing age. Regulatory Toxicology and Pharmacology 110: 104516.
3. Flannery, B.M. and Middleton, K.B. (2022). Updated interim reference levels for dietary lead to support FDA's Closer to Zero action plan. Regulatory Toxicology and Pharmacology 133: 105202.
4. Carrington, C. D. and Bolger, P. M. (1992). An assessment of the hazards of lead in food. Regulatory Toxicology and Pharmacology 16(3): 265–272.
5. Dolan, L. C., Flannery, B. M., Hoffman-Pennesi, D., Gavelek, A., Jones, O. E., Kanwal, R., Wolpert, B., Gensheimer, K., Dennis, S. and Fitzpatrick, S. (2020). A review of the evidence to support interim reference level for dietary lead exposure in adults. Regulatory Toxicology and Pharmacology 111: 104579.
6. FDA (2024b). Lead in food and foodwares. Available at: https://www.fda.gov/food/environmental-contaminants-food/lead-food-and-foodwares
7. H.R., Flannery, B. M., Crosby, L. M., Pouillot, R., Santillana Farakos, S.M., Van Doren, J.M., Dennis, S. Fitzpatrick, S. and Middleton, K. (2023). Reassessment of the cadmium toxicological reference value for use in human health assessments of foods. Regulatory Toxicology and Pharmacology 144: 105487.
8. FDA (2024c). Arsenic in food Available at: https://www.fda.gov/food/environmental-contaminants-food/arsenic-food#:~:text=The%20FDA%E2%80%99s%20goal%20is%20to%20limit%20consumer%20exposure,developing%20regulations%2C%20action%20levels%2C%20and%20providing%20education%20information.
9. FDA (2024d). Advice about eating fish. Available at: https://www.fda.gov/food/consumers/advice-about-eating-fish.