Potassium iodide (KI) dosing in a nuclear emergency

Concerns about a possible nuclear accident in the Ukraine are fueling interest in dosing potassium iodide (KI) to protect the thyroid gland.

An acute overdose of potassium iodine (KI) protects the thyroid gland from harm during a nuclear emergency.

There are signs that some Europeans are already stocking up on high-dose KI tablets designed for radiologic emergencies. The Globe and Mail reports

“Europeans scrambling to find iodide pills amid fears of nuclear blast in Ukraine” (March 1, 2020).

Even in Canada, located many thousands of kilometers away from Ukraine, people are feeling concerned and are purchasing emergency-strength KI pills in advance of their being needed. A supplier of emergency KI tablets called “RadBlock” has placed a notice on the tablet website saying this: “Please be aware that due to the volume of orders for RadBlock that shipping times will be over a week from placing of orders. We are doing our best, thank you” (KI Canada, Ltd).

To alleviate unnecessary panic, everyday citizens and thyroid patients need to understand enough to know when they are, and are not at risk.

During an emergency, experts and authorities play a leadership role in providing knowledge and emergency management plans. But knowledgeable citizens participate in executing those plans at the personal level. There’s a lot of knowledge already available today, and learning is easier when we are not in distress.

If you have a thyroid, you play a role in defending its health every day. Some decisions are entirely within your control, such as avoiding iodine deficiency and excess throughout your life.

Therefore, this article not only provides information specific to KI dosing in nuclear emergencies. It also covers scientific information about the health risks of iodine excess even when there is no state of emergency.

What do the experts & officials say?

In summary:

1. Now (March 4, 2022) is not the time to panic. Now is the time to learn.
2. If you live or work in a “primary zone” around a nuclear reactor, health authorities should give you access to some “emergency iodine” tablets with the appropriate strength.
3. Emergency KI dosing requires a very large single dose, and it is dosed by age group.
4. Timing matters. Don’t take your emergency KI overdose until the signal arrives.
5. Don’t take the emergency KI dose for a longer period of time than directed.
6. Iodine overdose can be risky if you have certain types of thyroid diseases or health conditions.
7. The risks of damage to the thyroid may outweigh the risk of emergency KI dosing.

Listen, learn and prepare.

This Canadian government page explains a lot about potassium iodide in the event of a nuclear emergency:

• Canadian Nuclear Safety Commission. (2016, July 11). Potassium iodide (KI) pills. Government of Canada. https://nuclearsafety.gc.ca/eng/resources/educational-resources/feature-articles/potassium-iodide-KI-pills.cfm

At the top of the page is a notice in pink shading, saying

“We are actively monitoring the events in Ukraine and are working closely with our federal and international counterparts to offer assistance.

Read our full statement for details on the coordinated effort.“

(Canadian Nuclear Safety Commission, 2016)

The notice was updated within 1 hour after I took the screenshot below:

They explain that

“KI saturates your thyroid gland, preventing radioactive iodine from being absorbed; over time, the radioactive iodine will decay and be harmlessly excreted in urine.”

(Canadian Nuclear Safety Commission, 2016)

The “RadBlock” tablets shown in the image are manufactured by KI Canada, Ltd, and can be ordered online here (we have no affiliation with this company).

A news outlet in Finland called Yle has published a notice from pharmacists saying there’s “No need to hoard iodine tablets.” However, the Finnish authorities are already prepared: “each housing company in Finland has an obligation to store iodine tablets for its residents.”

Another news outlet reported on March 4th, that

“As a precautionary measure, Ukrainian authorities are currently distributing iodine tablets to residents living near the Zaporizhzhia nuclear reactor, which was hit by a Russian shelling that caused a large fire at the site last night.” (The Times of Israel).

Echoing the “no panic” signal from Finland, the “statement” linked to the CNSC’s Ukraine notice explains there is no immediate cause for panic in Canada, and it’s not yet time to take KI pills, as of the time of writing (March 4, 2022):

“It is important to note there is no immediate radiological threat to the regions surrounding these facilities or to Canadians.

However, we support Canada’s status as a member state to the International Atomic Energy Agency (IAEA) and share in their grave concern regarding the ongoing situation and the risk to nuclear facilities. …

The IAEA is closely monitoring developments relating to nuclear facilities in the region, in line with its international mandate and continues to provide regular updates on the matter. We encourage you to visit their website about the conflict, and follow them on Twitter, LinkedIn or Facebook for the latest developments.”

(Canadian Nuclear Safety Commission, “CNSC Statement on the ongoing situation in Ukraine,” Date modified: 2022-03-04)

These international organizations are on the alert.

If or when the time comes to initiate acute iodine overdose, citizens will be notified by their governments and media.

Iodine vs. risk of radioactive iodine

Iodine is essential for thyroid gland health. Thyroid glands concentrate iodine and use it to synthesize thyroid hormones. T4 (thyroxine) hormone has 4 iodine atoms per molecule, and T3 (triiodothyronine) has 3 iodine atoms per molecule.

However, radioactive iodine in the environment poses a risk of thyroid cancer:

“The Chernobyl nuclear accident in 1986 exposed populations of Belarus, Ukraine, and the Russian Federation to internal radiation from radioactive iodines deposited in the thyroid, resulting in sharp increase in pediatric and adolescent thyroid cancer, mainly PTC [papillary thyroid cancer].”

(Zimmermann & Galetti, 2015)

“In the event of a nuclear emergency, KI is effective in reducing the threat of thyroid cancer to residents at risk of inhaling or ingesting radioactive iodine.”

(Canadian Nuclear Safety Commission, 2016)

Are you in the “zone” of proximity to a nuclear reactor?

In Canada, the concern is mainly for those living or working in the “primary zone” within 16.1 km from a nuclear reactor at the time of an accident that releases radioactive iodine into the air.

The “secondary zone” of risk is considered within 80 km of a nuclear reactor.

In comparison, European zones of proximity for pre-distribution of KI tablets vary from country to country.

“All countries having nuclear power plants in their territories are pre-distributing stable iodine.

The area for predistribution varies from 5 km radius around the NPP [nuclear power plant] to 50 km for the Ignalina NPP in Lithuania.

In most cases, stable iodine is delivered to the whole population. Pre-distribution may be of the responsibility of NPP operators or of local authorities.”

(European Commission, 2010)

Compare that to this:

“The Canadian Nuclear Safety Commission (CNSC) has mandated that all residents within the primary zone of a nuclear installation have the [potassium iodide] pills available in their homes.” (CBC News, 2018)

In Canada, we have 5 nuclear power plants:

• Bruce Nuclear Generating Station, Ontario
• Pickering Nuclear Generating Station, Ontario
• Darlington Nuclear Generating Station, Ontario
• Gentilly-2 Nuclear Facility, Québec (recently shut down)
• Point Lepreau Generating Station, New Brunswick
  (CNSC, 2014)

In the “primary zone” of these plants, pills should be pre-distributed by authorities, or the residents are told they have to pick them up. Pre-distribution of KI pills was in the news in 2018.  

The “secondary zone” is an 80km radius, where pre-distribution of KI is not considered necessary. Concerns about being in the “secondary zone” of 2 power plants (CBC News, 2020)

Unnecessary panic by people in low-risk zones can cause problems with supply and demand of emergency KI pills.

In 2011, when there was a Japanese nuclear crisis, Alberta pharmacists delivered public notice that it was “Inappropriate to stock or sell potassium iodide for radiation sickness prevention” because iodine radiation could not reach Alberta. (Alberta College of Pharmacists, 2011)

What is the effective emergency dose required?

The product information for “RadBlock” brand KI says each tablet contains:

• 49.7 mg of potassium iodide.

RadBlock’s high dose of 49.7 mg per tablet is roughly 330 times the recommended daily iodine intake, which is 150 mcg, given that there are 1000 micrograms in each milligram (mg):

“150 mcg in adults, 220-250 mcg in pregnant women, and 250-290 mcg in breastfeeding women in the U.S.” 

(American Thyroid Association, 2013)

Why such a high dose of >600x the recommended daily intake in adults?

One needs a dose high enough to block radioactive iodine from entering the thyroid and causing cancer.

At the bottom of the CNSC’s Potassium iodide page, dosing information is given about dosing KI, presumably RadBlock tablets that contain 49.7 mg of KI:

Category	Dose	Total mg
Pregnant or breastfeeding women	2 tablets (1 single dose only)	~100 mg
Adults (18+)	2 tablets every 24 hours	~100 mg
Children (3-18)	1 tablet every 24 hours	~50 mg
Children (1 month – 3 years)	½ tablet daily crushed in food or fluids	~25 mg
Children (under 1 month)	¼ tablet dissolved in fluids (1 single dose only)	~12.5 mg

Similar doses are found in The European Commission Directorate-General for Energy (2010), which compared recommendations from various countries:

Emergency iodine tablets are normally needed to achieve these high doses.

Tablets designed to prevent overdose during daily intake do not contain enough. It would require ingestion of many tablets. The adolescent and adult dose of 100 milligrams (mg) is equal to 100,000 micrograms (mcg). For example:

• New Roots Herbal brand contains 800 mcg of elemental iodine per tablet. 100,000 divided by 800 would require dosing 125 tablets at once!

Instead, if ordering online, search Amazon or online pharmacies for “potassium iodide” and look for higher dosages in milligrams — “mg.” For example, IOSAT Potassium Iodide Tablets come in doses of 130 mg.

Caution regarding Lugol’s or iodine tinctures

A workshop by the World Health Organization (WHO) in the year 2000 cautioned that “Tincture of iodine is not a suitable alternative to tablets or solution of stable iodine (Lugol’s solution).”

Why not a “tincture”?

At emergency dose levels, the liquid iodine tincture is “known to be a non-optimal agent, due to its somewhat toxic free-iodine content” (Wikipedia). It should be diluted.

Use Lugols with caution, as a diluted solution:

“Because it contains free iodine, Lugol’s solution at 2% or 5% concentration without dilution is irritating and destructive to mucosa, such as the lining of the esophagus and stomach. Doses of 10 mL of undiluted 5% solution have been reported to cause gastric lesions when used in endoscopy” (Wikipedia).

Why have age-specific doses?

Risk of damage from nuclear radioactive iodine is higher in younger age groups, because they have a higher yearly cancer risk per unit of radiation dose, and a longer time span for cancer to occur.

Some European countries had exempted adults over 40 from KI dosing “in case of contra-indications as iodine allergy, disturbance in thyroid function or thyroiditis” (European Commission, 2010).

The Province of Ontario (Canada) published “Potassium Iodide (KI) Guidelines” in 2014 explained,

“For adults over 40, the scientific evidence suggests that ITB is not recommended or required unless doses to the thyroid are expected to exceed levels that would threaten thyroid function, which is about 5 Gy*.

Doses at such a high level are unlikely to occur far away from an accident site.

Also, the risk of radiation-induced thyroid cancer in persons over 40 is extremely low and decreases with age, while the risk of side effects from taking KI increases with age as the incidence of thyroid diseases is higher.

Persons over 40 should receive information about the risks of KI for their age group and then decide for themselves whether to take it or not.

(Ministry of Health & Long Term Care, Province of Ontario, 2014)

* NOTE: Gy stands for “Gray,” the SI unit for radiation doses.

Effective emergency dose timing

The timing of the acute iodine overdose matters, because thyroids behave differently under acute vs. chronic overdose.

Dosing too soon OR too late are both ineffective.

The radioactive iodine-blocking dose of KI needs to be in place before exposure to radioactive iodine (I-¹³¹). But the dose should not be taken more than 24 hours before exposure or its effectiveness is reduced.

This information was also expressed in table format by the Japanese guidelines:

Timing of administration	Protective effect
24 hours prior to exposure	90% or higher
8 hours after	40%
24 hours after	7%

Therefore, wait for the signal that your region is affected.

KI dosing should only be done when directed by the government, when radioactive iodine levels are significant due to an emergency.

“KI should only be taken when directed by public health officials. 

It works best when it is taken immediately before or as soon as possible after exposure.

(Canadian Nuclear Safety Commission, 2016)

An article for Japanese physicians in 2014 explained that

“If the radioactive iodine released by nuclear power facilities enters the human body through inhaling or ingestion it, approximately 10-30% of the amount incorporated will accumulate in the thyroid gland within 24 hours of contamination …

As the result of exposure to radiation from this radioactive iodine, thyroid cancer or other diseases may develop in four years to a few decades.” 

(Yoshida et al, 2015)

Duration of dosing

The number of doses and the time between doses may vary based on exposure duration.

Usually only one dose is required.

In Europe, in countries that mention second intake, a second dose may occur 24 hours after the first. “The second intake is sometimes only envisaged for the most radiosensitive population, i.e. newborns, young children, pregnant and breast feeding women,” and may exclude persons over 40 (European Commission, 2010)

In situations where multiple doses are required, the total cumulative dose over many days is usually limited to <1g (<1000 mg) (European Commission, 2010).

The risks of dosing high quantities of iodine

While preventing iodine deficiency is important, it’s equally important not to err on the side of iodine excess.

Unfortunately, it has become trendy in some health communities, even some thyroid patient communities, to overdose iodine. Recommendations for overdose often show a callous disregard for its health risks.

• Patients with thyroid disorders are quite vulnerable to disinformation and peer pressure to try iodine excess as a solution for chronic hypothyroid symptoms during therapy. They are often not aware that it may hinder or distort the function of their remaining healthy thyroid tissue, as described below.
• People with thyroid nodules are sometimes told online that they can melt away their nodules with high doses of iodine. Many do not realize that some nodules can become toxic under acute iodine dosing, and there are better, more scientific approaches, such as non-toxic doses of selenium and myo-inositol.
• If iodine overdose works well for a patient, they will sometimes become evangelists who persuade their peers to try it, without awareness of the real dangers it poses to their peers who may have genetic predisposition to thyroid autoimmunity or preexisting diagnoses of Hashimoto’s, atrophic thyroiditis, or Graves’ disease.

The American Thyroid Association published a “ATA Statement on the Potential Risks of Excess Iodine Ingestion and Exposure” back in 2013:

“Ingestion of greater than 1,100 mcg of iodine per day (Tolerable Upper Limits for iodine) (1) is not recommended and may cause thyroid dysfunction.

During pregnancy and lactation, the recommendations for the upper limit vary and range from 500-1,100 mcg of iodine daily (2).

In particular, infants, the elderly, pregnant and lactating women, and individuals with preexisting thyroid disease are susceptible to adverse effects of excess iodine intake and exposure (5).

The public is advised that many iodine, potassium iodide, and kelp supplements contain iodine in amounts that are up to several thousand times higher than the daily Tolerable Upper Limits for iodine.

The American Thyroid Association (ATA) advises against the ingestion of iodine and kelp supplements containing in excess of 500 mcg iodine daily for children and adults and during pregnancy and lactation.

Chronic iodine intake in amounts greater than the Tolerable Upper Limits should be closely monitored by a physician.

There is only equivocal data supporting the benefit of iodine at higher doses than these, including a possible benefit for patients with fibrocystic breast disease (6).

There is no known thyroid benefit of routine daily iodine doses in excess of the U.S. RDA.”

(American Thyroid Association, 2013)

Why caution about iodine doses >500 mcg per day?

It’s based on many decades of research from scientists all over the world. Research includes iodine consumption in regions like Norway, Japan and Korea where people often ingest iodine from seaweed.

See this graph by Wang et al, 2019, showing “U-shaped risk” across multiple high-quality research studies:

TPOab = Thyroid peroxidase antibody. This is elevated in Hashimoto’s thyroiditis, and it is often elevated in Graves’ disease and autoimmune atrophic thyroiditis.

TGab = Thyroglobulin antibody. Relatively fewer people with autoimmune thyroid disease (AITD) have elevated TGab, but when it is elevated, it offers confirmation of autoimmune thyroid disease, since it is less commonly found in people without AITD. See our post “The Spectrum of Thyroid Autoimmunity” for more information about these two antibodies and the TSH receptor antibody.

The urinary iodine concentration (UIC) roughly corresponds to iodine intake:

“Approximately 90% of iodine is excreted in the urine (1). Urinary iodine concentration (UIC)⁶ directly reflects dietary iodine intake and is the most common indicator used worldwide to assess iodine status.”

(Pearce & Caldwell, 2016)

Risk of iodine-induced HYPOthyroidism

Iodine overdose is a treatment for hyperthyroidism for a reason. Excess can temporarily block iodine uptake into the thyroid gland.

“Administration of iodine to patients with severe hyperthyroidism or thyroid storm is efficacious, as it results in an acute decrease in the release of thyroid hormones.”

(Leung & Braverman, 2014)

Leung & Braverman explain that “The underlying mechanism of iodine-induced hypothyroidism remains unclear,” but could be due to “a damaged thyroid as a result of previous pathological insults.”

They go on to list the conditions that increase risk of hypothyroidism induced by excess iodine:

“Susceptible patients include:

• those with autoimmune thyroid disease;

• a previous history of surgery, ¹³¹I or antithyroid drug therapy, for Graves disease;

• subacute thyroiditis;

• postpartum thyroiditis;

• type 2 amiodarone-induced thyrotoxicosis (AIT);

• hemithyroidectomy;

• IFNα therapy [Interferon α-targeted therapy];

• and concomitant use of potential goitrogens, such as lithium.”

(Leung & Braverman, 2014)

Leung & Braverman (2014) report that in Japan, “chronic exposure to excess iodine” can result in “adaptive mechanisms” like “delayed onset congenital hypothyroidism” in an infant after ingesting too much seaweed in pregnancy, and “smaller thyroid glands” in Japanese schoolchildren with high urinary iodine levels. Autoimmune hypothyroidism was found to be 12.1% in regions with iodine-rich seaweed consumption but 2.3% in other regions of Japan, among people who tested negative for thyroid antibodies.

Risk of iodine-induced HYPERthyroidism

In a book chapter titled “Prevention and Treatment of Iodine-Induced Thyrotoxicosis,” Kolcsár and Gáll explain that it does not require a massive iodine overdose to induce a state of thyrotoxicosis from a hypersecreting thyroid gland. It could simply arise due to eating too much seaweed:

“Individuals who consume large amounts of seaweed regularly are also exposed to the risk of iodine-induced hyperthyroidism [21, 22]. Several reports are available describing diet-induced thyrotoxicosis in patients consuming seaweed-containing foods or beverages [23].

Risk factors for iodine-induced hyperthyroidism include

• nontoxic or diffuse nodular goiter,
• latent Graves’ disease, and
• long-standing iodine deficiency [24].”

(Kolcsár & Gáll, 2019)

It is wise not to be iodine-deficient before taking your KI overdose. Get your RDA of 150 mcg per day, which can be found in approximately 1/2 a teaspoon of iodized salt.

Kolscar & Gall explain further how thyroid nodules, induced by chronic iodine deficiency, can predispose the thyroid to respond to iodine excess by hypersecreting thyroid hormones:

“Iodine-induced hyperthyroidism (thyrotoxicosis) or Jod-Basedow effect is most frequently observed following iodine supplementation in individuals who had previously experienced severe iodine deficiency [15, 16].

A plausible explanation of this phenomenon can be the thyroid stimulating hormone (TSH) hyperstimulation of the thyroid gland, which may occur as an adaptive response to the iodine-deficient conditions and results in autonomous growth and function of thyrocyte clusters.

When iodine intake increases, these nodules may synthesize an excessive amount of thyroid hormones [10].

The mechanism consists of escape phenomenon when high doses of iodine are used for thyroid hormone synthesis, which can lead to severe thyrotoxicosis.

(Kolcsár & Gáll, 2019)

It is a common misconception that Japan does not have a problem with iodine excess from seaweed.

Risk vs. benefit must be reassessed in an emergency.

The CNSC is well aware that emergency KI overdose poses health risk in people with thyroid autoimmunity in particular, as well as “iodine deficiency/sensitivity”:

“The risk of health side effects associated with taking KI is very low for all age groups with regular thyroid function.

For people who have thyroid disorders (e.g., Graves’ disease, iodine deficiency/sensitivity and auto-immune thyroiditis), there is an increased risk of side effects. People who face an increased risk of side effects should consult a doctor or nurse prior to taking KI.

Overall, the benefit of taking the pill during a nuclear emergency far outweighs the risk of side effects. ”

(Canadian Nuclear Safety Commission, 2016)

You’ve now been informed.

• If the risk of exposure to environmental radioactive iodine is very low in your region, it is wise to avoid iodine overdose and just ensure you get your recommended intake per day.
• If you receive public health notification that exposure is imminent in your region, have your KI tablets on hand to initiate an acute loading dose at the right time.
• If you are over 40, assess your health risk based on the factors above, consulting with your doctor as needed.

References

Alberta College of Pharmacy. (2011, March 22). Inappropriate to stock or sell potassium iodide for radiation sickness prevention. https://abpharmacy.ca/articles/inappropriate-stock-or-sell-potassium-iodide-radiation-sickness-prevention

American Thyroid Association. (2013, June 5). ATA Statement on the Potential Risks of Excess Iodine Ingestion and Exposure. American Thyroid Association. https://www.thyroid.org/ata-statement-on-the-potential-risks-of-excess-iodine-ingestion-and-exposure/

Canadian Nuclear Safety Commission. (2022, March 4). CNSC Statement on the ongoing situation in Ukraine [Government of Canada]. https://www.canada.ca/en/nuclear-safety-commission/news/2022/03/cnsc-statement-on-the-ongoing-situation-in-ukraine.html

Canadian Nuclear Safety Commission. (2014, February 3). Nuclear power plants. https://www.cnsc-ccsn.gc.ca/eng/reactors/power-plants/index.cfm

Canadian Nuclear Safety Commission. (2016, July 11). Potassium iodide (KI) pills. Government of Canada. https://nuclearsafety.gc.ca/eng/resources/educational-resources/feature-articles/potassium-iodide-KI-pills.cfm

CBC News. (2018, April 26). Living in the nuclear plant’s “primary zone?” Health unit says there is a pill for that. CBC. https://www.cbc.ca/news/canada/windsor/health-unit-fermi-nuclear-plant-iodide-pill-1.4636438

CBC News. (2020, January 14). How Windsor-Essex would react to a nuclear emergency in Michigan. CBC. https://www.cbc.ca/news/canada/windsor/nuclear-emergency-windsor-essex-1.5425752

Dymling, J.-F., & Becker, D. V. (1967). Occurrence of Hyperthyroidism in Patients Receiving Thyroid Hormone. The Journal of Clinical Endocrinology & Metabolism, 27(10), 1487–1491. https://academic.oup.com/jcem/article-abstract/27/10/1487/2715287

European Commission Directorate-General for Energy. (2010). Medical effectiveness of iodine prophylaxis in a nuclear reactor emergency situation and overview of European practices. https://op.europa.eu/en/publication-detail/-/publication/fd7ed147-4336-4cb1-b739-d469dcffe8fb

Kolcsár, M., & Gáll, Z. (2019). Prevention and Treatment of Iodine-Induced Thyrotoxicosis. In N. K. Agrawal (Ed.), Goiter. IntechOpen. https://doi.org/10.5772/intechopen.89615

Leung, A. M., & Braverman, L. E. (2014). Consequences of excess iodine. Nature Reviews. Endocrinology, 10(3), 136–142. https://doi.org/10.1038/nrendo.2013.251

Pearce, E. N., & Caldwell, K. L. (2016). Urinary iodine, thyroid function, and thyroglobulin as biomarkers of iodine status123. The American Journal of Clinical Nutrition, 104(Suppl 3), 898S-901S. https://doi.org/10.3945/ajcn.115.110395

Province of Ontario, Emergency Management Branch, & Ministry of Health and Long-Term Care. (2014). Potassium Iodide (KI) Guidelines. https://www.health.gov.on.ca/en/pro/programs/emb/rhrp/docs/ki_guidelines.pdf

Wang, B., He, W., Li, Q., Jia, X., Yao, Q., Song, R., Qin, Q., & Zhang, J. (2019). U-shaped relationship between iodine status and thyroid autoimmunity risk in adults. European Journal of Endocrinology, 181(3), 255–266. https://doi.org/10.1530/EJE-19-0212

World Health Organization. (2000). WORKSHOP ON STABLE IODINE PROPHYLAXIS AFTER NUCLEAR ACCIDENTS. https://apps.who.int/iris/bitstream/handle/10665/108423/E73140.pdf?sequence=1&isAllowed=y

Yoshida, S., OJINO, M., OZAKI, T., HATANAKA, T., NOMURA, K., ISHII, M., KORIYAMA, K., & AKASHI, M. (2014). Guidelines for Iodine Prophylaxis as a Protective Measure: Information for Physicians. Japan Medical Association Journal : JMAJ, 57(3), 113–123. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4356652/

Zimmermann, M. B., & Galetti, V. (2015). Iodine intake as a risk factor for thyroid cancer: A comprehensive review of animal and human studies. Thyroid Research, 8, 8. https://doi.org/10.1186/s13044-015-0020-8