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Maricel V. Maffini, PhD’s Blog

Thyroid and kids' brains: Using modern tools to screen food chemicals

Maricel V. Maffini, PhD

Posted June 17, 2014

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The thyroid gland is one of those organs that some of us may have heard about, but the majority of us don’t know where it is in the body or exactly what it does. For those of us in the latter category — maybe it’s time to get to know our thyroid.

The thyroid gland sits on our neck hugging the wind pipe; it makes hormones called T3 and T4 depending on whether the molecule has 3 or 4 iodine atoms in it. Thyroid hormones have many important functions including:

  • Playing a critical role in proper development of fetal and infant brains; 
  • Regulating how the body uses energy from sugar, fat and proteins; and
  • Controlling proper cell development and differentiation (the process that enables less specialized cells to become more specialized liver, heart or brain cells, for example).

 The American Academy of Pediatrics’ Council on Environmental Health has just released a policy statement noting that “Adequate thyroid hormone production is critical in pregnant women and neonates because thyroid hormone is required for brain development in children.” Studies show that children born to mothers with low thyroid hormone have slow cognitive responses and impaired mental and motor development. The poster chemical for toxic effects on the thyroid is perchlorate. Perchlorate interferes with thyroid hormone function, likely causing neurodevelopmental problems in children. Even though the science behind perchlorate’s adverse effects on the thyroid is indisputable, and its mechanism is well understood,  FDA approved its use as an anti-static agent in food containers in 2005. Want your confectionary sugar not to stick to the bag? Perchlorate does the trick!

Thyroid hormones, like most hormones, work by binding to its receptor — similar to how a key fits a lock.  When the hormone (key) binds to the receptor (lock), the cell responds by making proteins, storing fat, and conducting similar cellular functions. Unfortunately, though, not all locks are perfect: chemicals (keys) other than natural hormones may fit in the lock and initiate similar effects as the intended hormone; these are called ‘activators’ because they activate the receptor and elicit a response that mimics the hormone in the body. Others can jam the lock and prevent the hormone from binding to its receptor and doing its job; these chemicals are called ‘inhibitors’. Chemicals that cross the placenta and inhibit the binding of maternal thyroid hormone to its receptor in the fetus’ brain, or block the newborn’s thyroid hormone from binding to its receptor, could potentially be damaging to brain development.  

Previously, we showed that there are 24 chemicals used as food ingredients that FDA identified in its own database as having adverse effects in the thyroid gland. But we know that less than 22% of the thousands of chemicals used as food ingredients have relevant toxicology information in FDA’s database. One alternative to fill in this massive data gap is to screen chemicals using new technologies that do not involve traditional animal testing, such as those developed under the Tox21 program — a multi-agency (including FDA) effort to quickly and efficiently identify potential toxic effects for thousands of chemicals that lack information.  

To date, Tox21 has run nearly 8,000 chemicals (including chemicals in food and consumer products and drugs) through hundreds of tests (including interactions with the thyroid receptor), and has made these data available to the public. Nearly 1,800 chemicals reacted with the thyroid hormone receptor, and we checked to see how many of these chemicals were allowed in food and whether they were inhibiting or activating the receptor.

We identified 259 chemicals allowed in food or food packaging that the Tox21 data indicate were active in the thyroid receptor assays (based on data published in PubChem here and here):

  • 26% (66 chemicals) were direct additives or food ingredients (these are chemicals added on purpose to the food and commonly listed as ingredients);
  • 41% (107 chemicals) indirect additives or food contact substances (these are chemicals that can get into the food through the manufacturing process or leaching from packaging material); and
  • 33% (86 chemicals) were pesticides used in agriculture that can end up in our food (more on food contact substances and pesticides on follow-up blogs - stay tuned!).

Of the 66 food ingredients that were active, 59 inhibit and 7 activate the function of the thyroid receptor. Fifty-nine percent (39 chemicals) of these ingredients were flavors (See the full list below). Four of the 66 food ingredients that were inhibitors of the thyroid receptor —ethoxyquin, FD&C Red No. 3, heptyl paraben and vitamin D3 — were already identified by FDA as having an adverse effect on the thyroid in animal studies. Some of you might be thinking, “Wait, isn’t vitamin D3 good for me?” Yes, in the right amount it can be good for you. Vitamins, like many other natural and man-made chemicals may have a range of safe doses outside which too much may cause harmful effects. Toxicology helps us identify the highest amount of an additive that can be consumed without causing adverse effects.

It’s worrisome that at any given time, a pregnant woman or a child may be assaulted by a slew of chemicals, all affecting their thyroid system. Each individual chemical may or may not have a harmful effect, but the real concern is that we know next to nothing about the cumulative effect of how being exposed to multiple chemicals can impact thyroid hormones and their ability to support the healthy development of a child’s brain.  A cumulative effect occurs when two or more chemicals affect the same tissue, organ or system in the body.

Although each chemical by itself may not cause adverse effects in, let’s say the thyroid, combining multiple chemicals also affecting the same system could potentially add up to harm. With so many additives targeting the thyroid gland, shouldn’t FDA be reassessing them based on their cumulative effect — basically doing what Congress required the agency to do in 1958? (the food additives law requires such cumulative effect analyses, see 21 U.S.C. §348(c)(5) and 21 CFR 170.3(i)). The chemicals red-flagged by Tox21 data for thyroid receptor deserve additional scrutiny.

Fast and efficient screening methods such as Tox21 are important sources of much-needed information for thousands of chemicals in food without any toxicity data. While the Environmental Protection Agency has published its thinking of what the 21st century risk assessment should look like in light of new and emerging knowledge and data produced using new technologies, FDA has been quiet. To my knowledge, the agency has made no use of these tests, and hasn’t even asked its Food Advisory Committee for advice on how to consider this massive amount of important new data. It’s time for FDA to break the silence and tell us how it will use Tox21 data, and how the agency will harness these new technologies to design a chemical safety reassessment program based on cumulative toxic effects. We need to hear your voice, FDA!

Food ingredients that reacted with the thyroid receptor assays in Tox21

Chemical Name CAS Number Action on thyroid receptor Use
(2Z)-3,7-Dimethylocta-2,6-dien-1-ol 106-25-2 Activator Flavor
(3aR)-(+)-Sclareolide 564-20-5 Inhibitor Flavor
(E,E)-2,4-Decadienal 25152-84-5 Inhibitor Flavor
1-(6-tert-Butyl-1,1-dimethyl-2,3-dihydro-1H-inden-4-yl)ethanone 13171-00-1 Inhibitor Flavor
1H-3a,7-Methanoazulen-6-ol, octahydro-3,6,8,8-tetramethyl-, (3R,3aS,6R,7R,8aS)- 77-53-2 Inhibitor Flavor
1-Undecanol 112-42-5 Inhibitor Flavor
2,4-Hexadienyl isobutyrate 16491-24-0 Inhibitor Flavor
2-Methoxycinnamaldehyde 1504-74-1 Inhibitor Flavor
2-Octanol 123-96-6 Activator Flavor
2-Propylphenol 644-35-9 Inhibitor Flavor
3,7-Dimethyl-2,6-octadienal 5392-40-5 Inhibitor Flavor
3,7-Dimethyloctane-1,7-diol 107-74-4 Activator Flavor
Acetaldehyde 75-07-0 Inhibitor Flavor
Acetyl tributyl citrate 77-90-7 Inhibitor Flavor
Allyl Ionone 79-78-7 Inhibitor Flavor
Benzyl cinnamate 103-41-3 Inhibitor Flavor
Benzyl phenylacetate 102-16-9 Inhibitor Flavor
Bicyclo[4.1.0]hept-3-ene, 3,7,7-trimethyl- 13466-78-9 Inhibitor Flavor
Bis(2-methyl-3-furyl)disulfide 28588-75-2 Inhibitor Flavor
Butylated hydroxytoluene 128-37-0 Inhibitor Flavor
Cananga oil 68606-83-7 Inhibitor Flavor
Diallyl trisulfide 2050-87-5 Inhibitor Flavor
Ethyl (2E,4Z)-deca-2,4-dienoate 3025-30-7 Inhibitor Flavor
Linalyl cinnamate 78-37-5 Inhibitor Flavor
Maltol 118-71-8 Activator Flavor
Methyl linoleate 112-63-0 Inhibitor Flavor
Nonivamide 2444-46-4 Inhibitor Flavor
Orange terpenes 8028-48-6 Inhibitor Flavor
Phenethyl isothiocyanate 2257-09-2 Inhibitor Flavor
Phenol 108-95-2 Activator Flavor
Sclareol 515-03-7 Inhibitor Flavor
Styrax balsam 8046-19-3 Inhibitor Flavor
Tannic acid 1401-55-4 Inhibitor Flavor
Linoleic acid 60-33-3 Inhibitor Flavor and edible oil replacement and emulsifier
Dodecanoic acid 143-07-7 Inhibitor Flavor and fruit coating
Sodium dodecyl sulfate 151-21-3 Inhibitor Flavor and fruit coating
Capsaicin 404-86-4 Inhibitor Flavor and pesticide
Farnesol 4602-84-0 Inhibitor Flavor and pesticide
Thymol 89-83-8 Inhibitor Flavor and pesticide
Carminic acid 1260-17-9 Inhibitor Color
FD&C Red 3 16423-68-0 Inhibitor Color
FD&C Green no. 3 2353-45-9 Inhibitor Color
Lutein 127-40-2 Inhibitor Color and nutrient
FD&C Blue no. 1 3844-45-9 Inhibitor Color and Pesticide
Genistein 446-72-0 Inhibitor Component in soy isoflavone ingredient
Glycocholic acid 475-31-0 Activator Emulsifier
Quercetin 117-39-5 Inhibitor Ingredient
Resveratrol 501-36-0 Inhibitor Ingredient
Sodium L-ascorbate 134-03-2 Activator Ingredient
Zeaxanthin 144-68-3 Inhibitor Ingredient
(-)-Epigallocatechin gallate 989-51-5 Inhibitor Ingredient
Ergocalciferol 50-14-6 Inhibitor Nutrient
Retinol 68-26-8 Inhibitor Nutrient
Vitamin D3 67-97-0 Inhibitor Nutrient
2',4',5'-Trihydroxybutyrophenone 1421-63-2 Inhibitor Preservative
di-tert-Butyl-4-hydroxymethyl phenol 88-26-6 Inhibitor Preservative
Dodecyl gallate 1166-52-5 Inhibitor Preservative
Heptylparaben 1085-12-7 Inhibitor Preservative
Octyl gallate 1034-01-1 Inhibitor Preservative
Sodium dehydroacetate 4418-26-2 Inhibitor Preservative
tert-Butylhydroquinone 1948-33-0 Inhibitor Preservative
Cetylpyridinium chloride 123-03-5 Inhibitor Preservative
Ethoxyquin 91-53-2 Inhibitor Preservative and Pesticide
Sodium dimethyldithiocarbamate 128-04-1 Inhibitor Secondary direct additive
Sodium dodecylbenzenesulfonate 25155-30-0 Inhibitor Secondary direct additive
Docusate sodium 577-11-7 Inhibitor Wetting agent
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