EDF Health

Broken GRAS: FDA’s lack of post-market oversight continues to create health risks

By Maricel Maffini, PhD, Consultant and Tom Neltner, Senior Director, Safer Chemicals Initiative / Published: July 11, 2023

What Happened?

In April, a company called Prime Research Reports issued a press release in which it claimed FDA had approved THP (tetrahydropiperine) as a Generally Recognized As Safe (GRAS) substance “for use in food products.” There is no record that FDA has either reviewed or approved THP for use in food.

The report describes Sabinsa as a manufacturer of THP and as “a major player” in that market.[1] The substance, commercially known as Cosmoperine, is derived from a highly purified extract from black pepper; the extract, which is more than 95% piperine, is also made by Sabinsa and is marketed as BioPerine. The company describes piperine as an alkaloid present in black and long pepper.

Why It Matters

First, the statement is at odds with the available evidence: there is no record of FDA reviewing the safety of THP as a GRAS substance. The only interaction we are aware of was in 2013, when Sabinsa voluntarily asked FDA to review its GRAS determination for BioPerine to be used as a flavoring agent. A few months later, Sabinsa sent a letter asking FDA to stop reviewing the safety assessment (also known as a “cease to evaluate” request). After that, there does not appear to have been any interactions between Sabinsa and FDA regarding either of its products.

Second, the statement mistakenly claims that FDA approves GRAS substances when in fact the agency issues an opinion when a manufacturer requests a review by FDA. In its opinion letters, the agency makes clear that it is not an approval.

Third, a decade ago, we identified significant safety concerns with BioPerine, the only product that FDA has had an opportunity to review although, as previously noted, that review was halted when Sabinsa withdrew its request for review. As a result, FDA did not issue an opinion. In 2013, the authors, on behalf of the Natural Resources Defense Council at the time, sent a letter to FDA listing many issues with the GRAS notice that Sabinsa had withdrawn, including:

  • Lack of toxicology testing for the extract, which is more than 95% piperine, the active ingredient.
  • Failure to correctly interpret toxicity data in the literature, which showed that piperine is toxic to the immune system and causes reproductive and developmental toxicity in animals and cell-based studies.
  • Dismissal of human studies showing that piperine affects the metabolism of other compounds including medications by increasing their bioavailability.

Piperine is “reported to enhance the bioavailability of drugs, nutrients, and herbal extracts,” and Cosmoperine is marketed as a “bioavailability enhancer.”

The presence of these substances in food could potentially increase the bioavailability of medications in ways that healthcare professionals prescribing the drug could not anticipate. As a result, the drug might have adverse health effects from the higher effective dose.

Our Take

It is clear that BioPerine and the related Cosmoperine are highly concentrated extracts from black pepper that have been neither adequately tested nor adequately evaluated to determine their uses are safe.

We have published multiple articles describing the problems with the GRAS process. Among the most egregious of FDA’s failures are:

  • Allowing companies to withdraw a GRAS notice where the company realizes that FDA may not give it a favorable review;
  • Not proactively making the concerns publicly available[2] about the safe use of the substance;
  • Not conducting any apparent post-market oversight when FDA has concerns about the safety of a chemical.

In our Broken GRAS series we show many examples of chemicals of dubious safety that stealthily entered the food supply without any warnings.

In January, FDA Commissioner Califf announced a “new and transformative vision for the FDA Human Food Programs” These are important steps, but a real measure is ensuring that GRAS substances where FDA had safety concerns are subjected to strong oversight to protect American’s health by restricting the use of harmful chemicals such as THP.

Next Steps

We have alerted FDA to the claims and asked the agency to quickly investigate this product and its uses to protect consumers–especially those who might be using one of the medications that are affected by THP. FDA responded that it “will take a closer look and make sure this information is routed as appropriate.” We will continue to press FDA to act expeditiously to get products like this one off the market until the agency can verify its safety.

[1] We don’t know the relationship between Prime Research Reports and Sabinsa and have not heard back on a request for information.

[2] The information may be available through a Freedom of Information Act but that does not mean it is publicly available since only the requester gets the information.

Also posted in Adverse health effects, Bioavailability, Broken GRAS, FDA, Food, GRAS, Health hazards, Industry influence, Risk assessment, Risk evaluation / Tagged , , , , , , | Authors: , / Read 1 Response

Is it time to rethink “lead-safe” and “lead-free”?

By Tom Neltner, Senior Director, Safer Chemicals Initiative / Published: June 30, 2023

By Tom Neltner, Senior Director, Safer Chemicals Initiative, Environmental Defense Fund and Charlotte Brody, National Director, Healthy Babies Bright Futures

Key Message

The scientific consensus is that there is no known safe level of lead exposure, and that no environment or home is truly free of lead.

With a few exceptions, we think it is time to retire the terms “lead-safe” and “lead-free” from our vocabulary. It sends conflicting messages to the public, consumers, and decision-makers. And it may undermine our efforts to reduce children’s exposure to lead from any source.

Rationale

Collectively, we have dedicated over a half-century to protecting children from lead. During that time, we and other advocates have used different terms to communicate our goals. Often, we drew our terms from the federal government. For example:

  • “Lead-free” has been used by Congress since 1986 to define drinking water pipes with no more than 80,000 parts per million (ppm) of lead. It kept the term in 2014 when it changed the level from 80,000 to 2,500 ppm. Similarly, FDA issued guidance in 2010 allowing a “lead-free” label on pottery if it meets the agency’s limits on lead.
  • “Lead-safe” is in the title for HUD’s 1999 rule to reduce lead-based paint exposure in federally assisted EPA also refers to “lead-safe work practices” in its 2008 renovation, repair and painting (RRP) rule for residential property. In addition, EPA created a “lead-safe” logo in 2010 for certified RRP firms. And HUD, EPA, and CPSC use the term in their pamphlet given to millions of families renting or buying homes built before 1978.

As a result, terms like “lead-safe” and “lead-free” have been commonly used to describe community-wide initiatives, label houses on maps, describe the state of a house after remediation, and much more.

What does lead-free mean? It depends on who you’re asking and what you’re asking about. A contractor may understand the term to mean that a house meets the EPA definition of not having a lead hazard, but does the average resident understand the term the same way? Is it accurate to describe a house as lead-free if there is still lead in the drinking water? Or in the spices in the cabinets?

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Also posted in Contamination, FDA, Lead, Public health, Unleaded Juice / Tagged , , , , | Authors: / Read 2 Responses

Unleading Baby Food: FDA’s proposed limits are a positive step, but…

By Tom Neltner, Senior Director, Safer Chemicals Initiative / Published: March 1, 2023

Tom Neltner, Senior Director, Safer Chemicals

What Happened: FDA recently released draft action levels for lead in foods intended for babies and young toddlers.1 Action levels represent the point above which FDA is likely to regard food as adulterated – essentially unsafe – and seek a recall. This is a key step in implementing FDA’s Closer to Zero Action Plan.

  • Lead limits would be 10 parts per billion (ppb) for most foods.
  • Limits would be 20 ppb for dry infant cereals and single-ingredient root vegetable products, because these products may have greater lead contamination levels. (Root vegetables are primarily carrots and sweet potatoes.)

The new action levels do not apply to juices; FDA proposed limits on those in April 2022.

Why It Matters: There is no safe level of lead in the diet.

For young children living in homes without lead pipes or lead paint, diet is the primary source of their lead exposure. FDA makes clear in the proposal that:

“Even low lead exposure can harm children’s health and development, specifically the brain and nervous system. Neurological effects of lead exposure during early childhood include learning disabilities, behavior difficulties, and lowered IQ. Lead exposures also may be associated with immunological, cardiovascular, renal, and reproductive and/or developmental effects. Because lead can accumulate in the body, even low-level chronic exposure can be hazardous over time.”

Lead can enter the food chain through multiple sources, including crops grown in contaminated soil and/or irrigated with contaminated water, atmospheric deposition from industrial activities, and old food-processing equipment that contains lead. The objective is to get exposure closer to zero.

Our Take: We applaud FDA’s proposed limits, which are more protective than the European Union’s 2021 standards. BUT…on the flip side:

  • FDA failed to set action levels for popular grain-based snacks, like teething biscuits and snack puffs. The agency needs to rectify this failure with all deliberate speed.
  • More protective action levels are achievable, especially for non-rice cereals and for foods that don’t contain rice or root vegetables.
  • Proposed action levels do not apply to multiple categories of foods, including:
  • FDA’s justification for the draft action levels lacks transparency—undermining both credibility of the levels and the likelihood industry will comply with them.

In addition, USDA and industry need to expand their support for research on the methods for growing, harvesting, and processing root vegetables, rice, and quinoa to further reduce lead contamination in these important foods. Research should include both store-bought and homemade baby foods.

Go Deeper: Visit our new Deep Dives blog to see our 3-part series, which provides a more detailed analysis of FDA’s proposal—including our recommendations for setting more protective limits and improving the transparency and credibility of the agency’s process of setting action levels.

NOTES
1 FDA’s guidance refers to babies and young children. Younger than two is a very narrow definition of young children, especially since children up to age six are particularly vulnerable to the harm that lead causes to their brains. Other federal agencies set standards for this broader age range. Toddlers are generally considered to be between 1 and 3 years of age. Therefore, we use the term “young toddlers” to avoid confusion.

Revised on March 21 to correct quote.

Also posted in Deep Dives, FDA, Health policy, Health science, Public health, Unleaded Juice / Read 1 Response

Unleaded Juice: FDA’s challenge of continuous improvement and compliance assurance

By Tom Neltner, Senior Director, Safer Chemicals Initiative / Published: October 2, 2022

Tom Neltner, Senior Director, Safer Chemicals

This is the sixth in our Unleaded Juice blog series exploring how the Food and Drug Administration (FDA) sets limits for toxic elements like lead, arsenic, and cadmium in food and the implications for the agency’s Closer To Zero program. 

A core tenet of FDA’s Closer to Zero program is the “Cycle of Continuous Improvement” represented by the image below on the program’s webpage. The four-stage, outer ring represents FDA’s process for revising its action levels for food contaminants. The inner, grey ring describes the agency’s on-going monitoring, research, and compliance program.


This approach makes sense, and we fully support it. However, the success of this approach relies on FDA addressing several significant structural weaknesses.

  • Future funding is not guaranteed: In March 2022, Congress appropriated $11 million in Fiscal Year 2022 (FY22) funding for FDA’s maternal and infant health work—in part to support the agency’s efforts to reduce arsenic, lead, and cadmium in children’s foods. Last year’s request and appropriations were a significant increase over previous years, but that funding level is not guaranteed for future years.
  • Action levels are guidance—not legally binding requirements: FDA’s action levels for contaminants in food are established in guidance. The guidance introduction makes it clear that “The contents of this document do not have the force and effect of law and are not meant to bind the public in any way, unless specifically incorporated into a contract.” It assumes that the food industry—from the largest multinational corporation to the smallest entrepreneur—will comply.
  • The agency has limited means to monitor compliance: FDA largely relies on physical inspections and market sampling, supplemented by voluntary reporting, to assure compliance with action levels. Inspections at high-risk facilities must occur every three years (but likely have been delayed due to the COVID pandemic). We understand that most facilities will see an inspector once every eight years. This is particularly problematic because FDA says it lacks the authority to require food companies to provide requested documents without the physical inspection, and the agency does not require ongoing testing and reporting by companies for action levels.
  • Action levels must be consistently strong enough to drive research and impact markets: FDA correctly points to its success in setting an action level for inorganic arsenic in infant rice cereal as a model to lower contamination. Unfortunately, the model assumes the action level for a contaminant is set low enough to result in research investments and increased product and ingredient testing and to provide FDA with sufficient information to act on problems. This is not the case for lead in juice.
     
    We explore each of these weaknesses below.

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Also posted in FDA, Lead, Public health, Unleaded Juice / Tagged , , , , | Comments are closed

Unleaded Juice: FDA needs to start with public health—not market impact

By Tom Neltner, Senior Director, Safer Chemicals Initiative / Published: September 22, 2022

Tom Neltner, Senior Director, Safer Chemicals 

This is the fifth in our Unleaded Juice blog series exploring how the Food and Drug Administration (FDA) sets limits for toxic elements like lead, arsenic, and cadmium in food and its implications for the agency’s Closer To Zero program. 

FDA’s approach to setting draft action levels for lead in juice is based on two ill-conceived presumptions:

  • Action levels should not impact more than 5% of the market. Unfortunately, FDA does not appear to consider market trends or whether the products were made using best practices shown to reduce contamination.
  • Action levels should help ensure 90% of young children have a dietary intake of lead that is below FDA’s Interim Reference Level, the maximum daily intake from food. Unfortunately, this effectively ignores the top 10% or 2.4 million of the most-exposed young children.[1]

To its credit, the agency has shown it is willing to go beyond the 5% impact for three types of juices (grape at 12%, pomegranate at 6%, and prune at 6%),[2] and it has proposed the most protective lead-in-juice standards in the world. However, for a heavy metal like lead where relatively short-term exposures can result in long-term harm to young children’s developing brains, the current approach has serious weaknesses.

We think the agency should evaluate alternatives that impact more than 5% of the market and protect more than 90% of children. And when FDA evaluates impacts, it should assess the socioeconomic benefits of the alternatives. For substances like lead (and arsenic), these societal benefits can be quantified using established methods. In a previous blog, we showed that reducing young children’s overall dietary intake of lead by just 6% would yield $1 billion a year in benefits. The agency should compare these benefits to the investments that industry would need to make to achieve these action levels using best practices.

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FDA Acknowledged Ortho-Phthalates Could Be Grouped Into Classes For Safety, Then Punted

By Tom Neltner, Senior Director, Safer Chemicals Initiative / Published: September 16, 2022

Maricel Maffini, consultant and Tom Neltner, Chemicals Policy Director

In May, FDA decided to allow continued use of nine ortho-phthalates in food packaging and processing equipment but punted on deciding whether or not using those phthalates is safe. We’ve written about the petitions that resulted in the decision, along with the agency’s decision to “abandon” the use of 19 other phthalates (here, here, here, and here). We’ve also written about how phthalates that industry and FDA say are no longer on the market are showing up in our food (here and here). Today, however, we focus on whether those nine phthalates are a class of related substances—and the implications for public health if they are.

FDA’s obligation to evaluate related chemicals as a class

FDA’s regulations state that additives “that cause similar or related pharmacological effects will be regarded as a class, and in the absence of evidence to the contrary, as having additive toxic effects.” In denying our petition, FDA acknowledged that some phthalates could be in a class of related substances. For example, FDA described studies showing that seven phthalates reduced testosterone production – an effect called antiandrogenicity – during fetal development. This caused malformation of the male reproductive system (primarily malformed genitals in male infants). The agency balked at declaring all phthalates anti-androgenic because four of them did not show that effect.[1]

But rather than move forward with a safety assessment of the use of the antiandrogenic phthalates as a class of chemicals with similar toxicity, FDA dropped the issue, implicitly sending the message the chemicals are safe. This is contrary to the agency’s obligation. When making a final decision on a food additive petition that allows the use of a substance, FDA must explicitly decide the use is safe after considering the cumulative effect of it and related substances in the diet.[2]

In contrast to FDA’s failure to act, the Consumer Product Safety Commission, responding to safety concerns, took action five years earlier and banned use of antiandrogenic phthalates in children’s products.

A phthalate scorecard: Where we stand on which phthalates can be used and their health effects

The table below provides a scorecard for the nine phthalates that remain in use. Of those substances, studies showed that seven were associated with developmental effects, including four which have antiandrogenic effects. Two phthalates were never studied for developmental effects.

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