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Maricel V. Maffini, PhD’s Blog

Overloaded: approaches to assess cumulative effects of food additives on brain development

Maricel V. Maffini, PhD

Posted July 2, 2014

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In 2011, Center for Disease Control and Prevention reported about the upward trend in the prevalence of developmental disabilities including autism, attention deficit hyperactivity disorder and other developmental delays in a 12-year period. Approximately 1 in 6 children has a developmental disability requiring more health care and education services. Why is this happening?

A common cause of neurodevelopmental problems is exposure to chemicals during brain development. The brain is such an exquisite organ that even very small or short disruptions to its normal development during the critical prenatal and early childhood periods can have terrible consequences years or decades later. The most pervasive source of chemicals is food; commonly known as “food additives”,  these are chemicals allowed to be added directly to food or that are in contact with food through packaging, manufacturing, or processing. Every time we eat, we are exposed to a complex mixture of chemicals; exposure begins even before we are born via our mom’s diet and it last our lifetime.

When Congress passed the Food Additives Amendment of 1958 it mandated that FDA is required to consider the following three factors in determining whether a chemical use is safe:

  • consumption information;
  • use of safety factors; and
  • the topic of this blog: The cumulative effect of the substance in the diet, taking into account any chemically or pharmacologically related substance or substances in such diet (21 U.S.C. 348(c)(5) & 21 CFR §170.3(i)). (emphasis added). In other words, "chemically related" means that the chemicals have similar structure, and "pharmacologically related" means that the chemicals produce similar biological effects.

But, what does cumulative effect mean? Simply put, it means that when two or more chemicals have an effect on the same organ or system it may result in harm; but each chemical individually may not cause harm. It is the combined effect(s) of chemicals on an otherwise healthy system that could potentially cause a health problem. Another way to think about this is to imagine that a wedding party wants to take a picture standing on a dock. Much like the effect(s) of chemicals on an organ, every person that steps on the dock puts some strain on one or more of its parts, but one person alone doesn’t necessarily cause any structural damage. As more people walk on the dock, though, the structure is more strained, potentially resulting in a collapsed dock (and a bunch of screaming, wet people). In the same way, multiple chemicals affecting the brain throughout its development may cause serious harm such as developmental disabilities when one alone may be fine.

Although chemicals can interact in a number of ways, including working together or working against each other, FDA clearly stated in 1959 that: “[f]ood 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 and will be considered as related food additives.” (21 CFR §170.18) (emphasis added). In other words, the default assumption is that the effects caused by two or more chemicals on the same organ, tissue or system would be greater than the effects caused by an individual chemical alone.  Additionally, their combined effect is greater not necessarily because they cause the same injury, but because they injure the same organ.

Now, think of chemicals that individually are known to affect the developing brain. Doesn’t it make sense to evaluate their safety together to prevent the potentially devastating consequences of their cumulative effects on children’s health? Unfortunately, cumulative effect is the forgotten factor in the safety assessment of chemicals. I’m not saying it’s easy to do but it’s hard when FDA considers chemicals on a case-by-case basis and there is no systematic review of old safety decisions that will give the agency a big picture of chemical uses in the diet.

In my previous blog, I mentioned 44 food additives that FDA identified as having adverse effects on the brain and the thyroid gland (as a quick refresher - without normal thyroid hormones, fetal and infant brain development is impaired). According to FDA’s rule (21 CFR §170.18), “[t]olerances established for such related food additives may limit the amount of a common component that may be present, or may limit the amount of biological activity (such as cholinesterase inhibition) that may be present or may limit the total amount of related food additives that may be present.” In FDA parlance, the word “tolerance” refers to a safe level of consumption.

What FDA did not establish is a method to group related food additives based on their cumulative biological effects. Selecting the criteria for identifying food additives that are pharmacologically related because they have similar biological effects on the same organs or systems is the first step in cumulative effect assessment. A number of organizations have used or proposed a number of methods. For instance:

1- U.S. Environmental Protection Agency (EPA): The EPA Office of Pesticide Program (OPP) developed guidance to “assess the cumulative risks to human health that can result from exposure to pesticides and other substances that are toxic by a common mechanism” as required by the Food Quality Protection Act (FQPA) of 1996. In 1999, OPP published its method to group chemicals within a class narrowly focused on the mechanism of toxicity of each pesticide. This means that chemicals would be grouped based upon how the chemicals cause harmful effects, rather than focusing on a particular harmful effect regardless of how it is caused.

This approach may be logical when we know how chemicals cause harm, but all too often our search for the mechanisms of toxicity has resulted in more questions than answers. Unfortunately, in the absence of these types of data, EPA’s approach is to assume that chemicals work through different mechanisms and, therefore, they won’t be evaluated together. I think that approach is shortsighted.     

2-  National Research Council (NRC): In 2008, at the request of EPA, the NRC (the working arm of the U.S. National Academy of Sciences) released its guidance for assessing cumulative risk assessment for pharmacologically related chemicals with similar biological effects. The report recognized the need for a broader approach to grouping chemicals with similar effects by focusing on “health outcomes and not in the pathways that lead to them”. The NRC expert committee based its recommendation on our limited knowledge about how molecules interact to cause harm within the body. For example, we know that food ingredients such as ethoxyquin, FD&C Red No. 3 and heptyl paraben individually cause adverse effects in the thyroid system in animals, and disrupt thyroid hormone function by blocking its binding to the thyroid receptor in cell-based studies. By either mechanism, thyroid hormone function is disrupted  potentially damaging the developing brain and causing severe health problems. The NRC approach makes total sense.

3- European Food Safety Authority (EFSA): Last year, EFSA released a methodology to identify pesticides with similar toxic effects. The first two systems the committee of experts focused on were the nervous and the thyroid systems. EFSA’s methodology is broad and similar to the NRC approach; the experts stated that “[i]n the interest of consumer protection, a grouping approach which emphasizes common adverse outcomes was adopted…” The panel of experts not only designed the methodology, but put it into practice. This broad approach is designed to not exclude pesticides that contribute to common health effects. The experts explicitly rejected EPA’s narrow approach to pesticides evaluation.

As an example, for the thyroid system, the panel of experts grouped pesticides by two adverse effects: 1) decrease in circulating levels of thyroid hormone, or 2) decrease in hormone action in the body. The experts reasoned that these alterations in normal body functions may lead to health problems, including impairment of brain development. The panel also listed a number of specific effects used as “indicators” for impacts on the thyroid system. You can read their detailed analysis here.

Using this approach, EFSA’s panel of experts identified 68 pesticides allowed in food that impacted the thyroid system; only 7 of which have known mechanisms of action. If EFSA would have applied the strictest grouping method implemented by EPA, it would have missed at least 61 pesticides that may cause harm to the thyroid system. See the list of pesticides below including also those identified as having an impact on the nervous system.

EFSA could design a more health protective approach to cumulative effect because it doesn’t have the type of restrictions that FQPA imposed on EPA. And FDA is also free of the FQPA restrictions so that it could design a method closely related to EFSA’s. Additionally, Congress made it clear that FDA has to consider the cumulative effects of all pharmacologically-related substances in the diet. Because our diet is complex and we are exposed to multiple chemicals at once rather than one chemical at a time, it makes sense that in 1959 FDA pioneered the concept that two or more chemicals could be more toxic than each in isolation. Unfortunately, the agency’s practices regarding food additives safety hasn’t advanced significantly since then.

FDA should design a systematic safety re-evaluation program that is based on common biological effects and cumulative toxicity. To do this, it should take a page from EFSA’s methodology and design a system to identify food additives to be included in cumulative assessment groups based on common adverse health outcomes - such as impairment of brain development. Understanding the health impact of chronic exposures to multiple chemicals in the diet is critical to reduce the disease burden and improve the well-being of future generations. We can’t waste more time to do what Congress mandated in 1958. The time has come to overhaul the way chemical safety assessment is done in the US.


Pesticides allowed in food in the US and the European Union

Thyroid system Nervous system EFSA pesticide name CAS number
Yes Yes 2,4-D 94-75-7
Yes Abamectin (aka avertin)

Yes Acetamiprip 135410-20-7
Yes Alpha-Cypermethrin (aka alphamethrin)
Yes Benfluralin 1861-40-1
Yes Benthiavalicarb
Yes Beta-Cyfluthrin
Yes Boscalid 188425-85-6
Yes Bromoxynil 1689-84-5
Yes Buprofezin 69327-76-0
Yes Carboxin 5234-68-4
Yes Yes Chlorpropham 101-21-3
Yes Chlorpyrifos 2921-88-2
Yes Chlorpyrifos-methyl 5598-13-0
Yes Clethodim 99129-21-2
Yes Clodinafop
Yes Clofentezine 74115-24-5
Yes Clothianidin 205510-92-5
Yes Cyflufenamid
Yes Cyfluthrin
Yes Cyhalofop-butyl 122008-85-9
Yes Cymoxanil 57966-95-7
Yes Cypermethrin
Yes Cyprodinil 121552-61-2
Yes Deltamethrin 52918-63-5
Yes Yes Desmedipham 13684-56-5
Yes Dicamba 1918-00-9
Yes Diclofop
Yes Dimethoate 60-51-5
Yes Dithianon 3347-22-6
Yes Dodine 2439-10-3
Yes Esfenvalerate 66230-04-4
Yes Ethephon 16672-87-0
Yes Etophenprox 80844-07-1
Yes Fenamidone 161326-34-7
Yes Fenamiphos (aka phenamiphos)
Yes Fenbuconazole 114369-43-6
Yes Fenpropidin
Yes Fenpropimorph 67564-91-4
Yes Yes Fipronil 120068-37-3
Yes Yes Flufenacet (formely fluthiamide)
Yes Flumioxazin 141490-50-8
Yes Fluopicolide 239110-15-7
Yes Fluoxastrobin 361377-29-9
Yes Flutolanil 66332-96-5
Yes Folpet 133-07-3
Yes Yes Formetanate
Yes Fosthiazate 98886-44-3
Yes Glufosinate
Yes Hexythiazox 78587-05-0
Yes Imazosulfuron
Yes Yes Imidacloprid 138261-41-3
Yes Indoxacarb 173584-44-6
Yes Yes Isoxaflutole 141112-29-0
Yes Lambda-Cyhalothrin
Yes Malathion 121-75-5
Yes Maleic hydrazide 123-33-1
Yes Yes Mancozeb 8018-01-7
Yes Yes Maneb 12427-38-2
Yes MCPA 94-74-6
Yes Mepanipyrim 110235-47-7
Yes Mepiquat
Yes Metaldehyde 108-62-3
Yes Methomyl 16752-77-5
Yes Yes Metiram
Yes Metribuzin 21087-64-9
Yes Myclobutanil 88671-89-0
Yes Oryzalin 19044-88-3
Yes Oxamyl 23135-22-0
Yes Oxyfluorfen 42874-03-3
Yes Pendimethalin 40487-42-1
Yes Penoxsulam 219714-96-2
Yes Phosmet 732-11-6
Yes Picloram 1918-02-1
Yes Pirimiphos-methyl 29232-93-7
Yes Propamocarb
Yes Propyzamide 23950-58-5
Yes Proquinazid
Yes Prothioconazole 178928-70-6
Yes Pymetrozine 1233112-89-0
Yes Yes Pyrethrins 977009-49-6
Yes Yes Pyridate 55512-33-9
Yes Pyrimethanil 53112-28-0
Yes Quizalofop-P (including ethyl and tefuryl)
Yes Yes Spinosad 131929-63-0
Yes Spirodiclofen 148477-71-8
Yes Sulfuryl fluoride 2699-79-8
Yes tau-Fluvalinate 102851-06-9
Yes Tefluthrin 149979-41-9
Yes Tepraloxydim 149979-41-9
Yes Tetraconazole 112281-77-3
Yes Thiabendazole 148-79-8
Yes Yes Thiacloprid 111988-49-9
Yes Yes Thiamethoxam 153719-23-4
Yes Thiophanate-methyl 23564-05-8
Yes Yes Thiram 137-26-8
Yes Tolylfluanid 731-27-1
Yes Triadimenol
Yes Tri-allate
Yes Tribenuron (aka metometuron)
Yes zeta-Cypermethrin
Yes Yes Ziram (including imputiry TMTU)
Yes Zoxamide 156052-68-5
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Dawn Riccardi MorrisJul 2 2014 09:29 PM

Thank you so much for pointing out that "the most pervasive source of chemicals is food." People don't understand that if their child is eating the same products every day, they are taking in a lot of the same chemicals repeatedly. There is no way to know how that would affect any one of us, especially our children.

Donna Jackson Nakazawa speaks of the "barrel effect" in her book, The Autoimmune Epidemic. As we take in small amounts of various toxins over time, eventually the barrel will overflow and we will get sick. It's shocking that newborns are already born with some of that barrel already full!

Food is the one thing parents can control, as far as toxins go. So, we all need to eat REAL, organic, additive free food. Thanks again for raising awareness!

barry DennisJul 7 2014 06:01 PM

I, too, have found it illogical to separate the effect of one chemical from the cumulative effects of multiple chemicals used in food processing and storage. Many of these chemical find their way into different organs, and body systems, accumulate or cause immediate change, and ongoing research shows generationally higher levels of those chemicals that have a demonstrated synergistic effect on organs systems, particularly brain and reproductive systems.
It was in pursuit of a simple question (your question as well) that I wrote "We Need Zero Sum Pollution Now" in which I postulated that NO CORPORATION, NO BUSINESS ENTITY, NO COMMERCIAL ENTERPRISE, NO GOVERNMENT ENTITY had-or has- a right to pollute air, food and water merely by the provisioning of a license to do business. By some estimates the cumulative social and health costs of such chemicals are in the Trillions of dollars; that's Trillions with a big "T" folks!
Further, I offered that legislative remedies should be immediately offered at the national level which requires no new business licenses without Zero Sum Pollution as a licensing condition, AND that All existing business must develop a twenty year plan to achieve Zero Sum Pollution through replacement of plants and equipment, air and water treatment as necessary, and end-to-end recycling/reclamation TO HIGHEST END VALUE of all waste materials.

EchoJul 9 2014 12:36 AM

Interesting. I just know "cumulative effect". In China, no food is guaranteed. So we always say there is already the antibody in our body for we've eaten much toxical food so that we are more resistant to unhealthy food than people in other country. I don't know if this is right.

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