Tag Archives: colorectal cancer

Findings on oral exposure to nanoscale titanium dioxide

It’s been a while since I’ve run a piece on health concerns and nanoparticles. The nanoparticles in question are titanium dioxide and the concerns centre on oral exposure to them according to a Jan. 24, 2017 news item on Nanowerk,

Researchers from INRA [French National Institute for Agricultural Research] and their partners have studied the effects of oral exposure to titanium dioxide, an additive (E171) commonly used in foodstuffs, especially confectionary. They have shown for the first time that E171 crosses the intestinal barrier in animals and reaches other parts of the body.

Immune system disorders linked to the absorption of the nanoscale fraction of E171 particles were observed. The researchers also showed that chronic oral exposure to the additive spontaneously induced preneoplastic lesions in the colon, a non-malignant stage of carcinogenesis, in 40% of exposed animals.

Moreover, E171 was found to accelerate the development of lesions previously induced for experimental purposes. While the findings show that the additive plays a role in initiating and promoting the early stages of colorectal carcinogenesis, they cannot be extrapolated to humans or more advanced stages of the disease. [emphasis mine]

A Jan. 20, 2017 IINRA press release, which originated the news item,  provides more detail about European use of titanium dioxide as a food additive and about the research,

Present in many products including cosmetics, sunscreens, paint and building materials, titanium dioxide (or TiO2), known as E171 in Europe, is also widely used as an additive in the food industry to whiten or give opacity to products. It is commonly found in sweets, chocolate products, biscuits, chewing gum and food supplements, as well as in toothpaste and pharmaceutical products. Composed of micro- and nanoparticles, E171 is nevertheless not labelled a “nanomaterial”, since it does not contain more than 50% of nanoparticles (in general it contains from 10-40%). The International Agency for Research on Cancer (IARC) evaluated the risk of exposure to titanium dioxide by inhalation (occupational exposure), resulting in a Group 2B classification, reserved for potential carcinogens for humans.

Today, oral exposure to E171 is a concern, especially in children who tend to eat a lot of sweets. INRA researchers studied the product as a whole (that is, its mixed composition of micro- and nanoparticules), and have also evaluated the effect of the nanoscale particle fraction alone, by comparing it to a model nanoparticle.

Titanium dioxide crosses the intestinal barrier and passes into the bloodstream

The researchers exposed rats orally to a dose of 10mg of E171 per kilogram of body weight per day, similar to the exposure humans experience through food consumption (data from European Food Safety Agency, September 20162). They showed for the first time in vivo that titanium dioxide is absorbed by the intestine and passes into the bloodstream. Indeed, the researchers found titanium dioxide particles in the animals’ livers.

Titanium dioxide alters intestinal and systemic immune response

Titanium dioxide nanoparticles were present in the lining of the small intestine and in the colon, and entered the nuclei of the immune cells of Peyer’s patches, which induce immune response in the intestine. The researchers showed an imbalance in immune response, ranging from a defect in the production of cytokines in Peyer’s patches to the development of micro-inflammation in colon mucosa. In the spleen, representative of systemic immunity, exposure to E171 increases the capacity of immune cells to produce pro-inflammatory cytokines when they are activated in vitro.

Chronic oral exposure to titanium dioxide plays a role in initiating and promoting early stages of colorectal carcinogenesis

The researchers exposed rats to regular oral doses of titanium dioxide through drinking water for 100 days. In a group of rats previously treated with an experimental carcinogen, exposure to TiO2 led to an increase in the size of preneoplastic lesions. In a group of healthy rats exposed to E171, four out of eleven spontaneously developed preneoplastic lesions in the intestinal epithelium. Non-exposed animals presented no anomalies at the end of the 100-day study. These results indicate that E171 both initiates and promotes the early stages of colorectal carcinogenesis in animals.

These studies show for the first time that the additive E171 is a source of titanium dioxide nanoparticles in the intestine and the entire body, with consequences for both immune function and the development of preneoplastic lesions in the colon. These first findings justify a carcinogenesis study carried out under OECD [Organization for Economic Cooperation and Development] guidelines to continue observations at a later stage of cancer. They provide new data for evaluating the risks of the E171 additive in humans.

These studies were carried out within the framework of the Nanogut project, financed by the French Agency for Food, Environmental and Occupational Health & Safety (ANSES) within the French national programme for research related to the environment, health and the workplace (PNR EST) and coordinated by INRA. Sarah Bettini’s university thesis contract was financed by the French laboratory of excellence LabEx SERENADE.

Here’s a link to and a citation for the paper,

Food-grade TiO2 impairs intestinal and systemic immune homeostasis, initiates preneoplastic lesions and promotes aberrant crypt development in the rat colon by Sarah Bettini, Elisa Boutet-Robinet, Christel Cartier, Christine Coméra, Eric Gaultier, Jacques Dupuy, Nathalie Naud, Sylviane Taché, Patrick Grysan, Solenn Reguer, Nathalie Thieriet, Matthieu Réfrégiers, Dominique Thiaudière, Jean-Pierre Cravedi, Marie Carrière, Jean-Nicolas Audinot, Fabrice H. Pierre, Laurence Guzylack-Piriou, & Eric Houdeau. Scientific Reports 7, Article number: 40373 (2017) doi:10.1038/srep40373 Published online: 20 January 2017

This paper is open access.

The research is concerning but they don’t want to draw any conclusions yet, which explains the recommendation for further research.

Sniffing out disease (Na-Nose)

The ‘artificial nose’ is not a newcomer to this blog. The most recent post prior to this is a March 15, 2016 piece about Disney using an artificial nose for art conservation. Today’s (Jan. 9, 2016) piece concerns itself with work from Israel and ‘sniffing out’ disease, according to a Dec. 30, 2016 news item in Sputnik News,

A team from the Israel Institute of Technology has developed a device that from a single breath can identify diseases such as multiple forms of cancer, Parkinson’s disease, and multiple sclerosis. While the machine is still in the experimental stages, it has a high degree of promise for use in non-invasive diagnoses of serious illnesses.

The international team demonstrated that a medical theory first proposed by the Greek physician Hippocrates some 2400 years ago is true, certain diseases leave a “breathprint” on the exhalations of those afflicted. The researchers created a prototype for a machine that can pick up on those diseases using the outgoing breath of a patient. The machine, called the Na-Nose, tests breath samples for the presence of trace amounts of chemicals that are indicative of 17 different illnesses.

A Dec. 22, 2016 Technion Israel Institute of Technology press release offers more detail about the work,

An international team of 56 researchers in five countries has confirmed a hypothesis first proposed by the ancient Greeks – that different diseases are characterized by different “chemical signatures” identifiable in breath samples. …

Diagnostic techniques based on breath samples have been demonstrated in the past, but until now, there has not been scientific proof of the hypothesis that different and unrelated diseases are characterized by distinct chemical breath signatures. And technologies developed to date for this type of diagnosis have been limited to detecting a small number of clinical disorders, without differentiation between unrelated diseases.

The study of more than 1,400 patients included 17 different and unrelated diseases: lung cancer, colorectal cancer, head and neck cancer, ovarian cancer, bladder cancer, prostate cancer, kidney cancer, stomach cancer, Crohn’s disease, ulcerative colitis, irritable bowel syndrome, Parkinson’s disease (two types), multiple sclerosis, pulmonary hypertension, preeclampsia and chronic kidney disease. Samples were collected between January 2011 and June 2014 from in 14 departments at 9 medical centers in 5 countries: Israel, France, the USA, Latvia and China.

The researchers tested the chemical composition of the breath samples using an accepted analytical method (mass spectrometry), which enabled accurate quantitative detection of the chemical compounds they contained. 13 chemical components were identified, in different compositions, in all 17 of the diseases.

According to Prof. Haick, “each of these diseases is characterized by a unique fingerprint, meaning a different composition of these 13 chemical components.  Just as each of us has a unique fingerprint that distinguishes us from others, each disease has a chemical signature that distinguishes it from other diseases and from a normal state of health. These odor signatures are what enables us to identify the diseases using the technology that we developed.”

With a new technology called “artificially intelligent nanoarray,” developed by Prof. Haick, the researchers were able to corroborate the clinical efficacy of the diagnostic technology. The array enables fast and inexpensive diagnosis and classification of diseases, based on “smelling” the patient’s breath, and using artificial intelligence to analyze the data obtained from the sensors. Some of the sensors are based on layers of gold nanoscale particles and others contain a random network of carbon nanotubes coated with an organic layer for sensing and identification purposes.

The study also assessed the efficiency of the artificially intelligent nanoarray in detecting and classifying various diseases using breath signatures. To verify the reliability of the system, the team also examined the effect of various factors (such as gender, age, smoking habits and geographic location) on the sample composition, and found their effect to be negligible, and without impairment on the array’s sensitivity.

“Each of the sensors responds to a wide range of exhalation components,” explain Prof. Haick and his previous Ph.D student, Dr. Morad Nakhleh, “and integration of the information provides detailed data about the unique breath signatures characteristic of the various diseases. Our system has detected and classified various diseases with an average accuracy of 86%.

This is a new and promising direction for diagnosis and classification of diseases, which is characterized not only by considerable accuracy but also by low cost, low electricity consumption, miniaturization, comfort and the possibility of repeating the test easily.”

“Breath is an excellent raw material for diagnosis,” said Prof. Haick. “It is available without the need for invasive and unpleasant procedures, it’s not dangerous, and you can sample it again and again if necessary.”

Here’s a schematic of the study, which the researchers have made available,

Diagram: A schematic view of the study. Two breath samples were taken from each subject, one was sent for chemical mapping using mass spectrometry, and the other was analyzed in the new system, which produced a clinical diagnosis based on the chemical fingerprint of the breath sample. Courtesy: Tech;nion

There is also a video, which covers much of the same ground as the press release but also includes information about the possible use of the Na-Nose technology in the European Union’s SniffPhone project,

Here’s a link to and a citation for the paper,

Diagnosis and Classification of 17 Diseases from 1404 Subjects via Pattern Analysis of Exhaled Molecules by Morad K. Nakhleh, Haitham Amal, Raneen Jeries, Yoav Y. Broza, Manal Aboud, Alaa Gharra, Hodaya Ivgi, Salam Khatib, Shifaa Badarneh, Lior Har-Shai, Lea Glass-Marmor, Izabella Lejbkowicz, Ariel Miller, Samih Badarny, Raz Winer, John Finberg, Sylvia Cohen-Kaminsky, Frédéric Perros, David Montani, Barbara Girerd, Gilles Garcia, Gérald Simonneau, Farid Nakhoul, Shira Baram, Raed Salim, Marwan Hakim, Maayan Gruber, Ohad Ronen, Tal Marshak, Ilana Doweck, Ofer Nativ, Zaher Bahouth, Da-you Shi, Wei Zhang, Qing-ling Hua, Yue-yin Pan, Li Tao, Hu Liu, Amir Karban, Eduard Koifman, Tova Rainis, Roberts Skapars, Armands Sivins, Guntis Ancans, Inta Liepniece-Karele, Ilze Kikuste, Ieva Lasina, Ivars Tolmanis, Douglas Johnson, Stuart Z. Millstone, Jennifer Fulton, John W. Wells, Larry H. Wilf, Marc Humbert, Marcis Leja, Nir Peled, and Hossam Haick. ACS Nano, Article ASAP DOI: 10.1021/acsnano.6b04930 Publication Date (Web): December 21, 2016

Copyright © 2017 American Chemical Society

This paper appears to be open access.

As for SniffPhone, they’re hoping that Na-Nose or something like it will allow them to modify smartphones in a way that will allow diseases to be detected.

I can’t help wondering who will own the data if your smartphone detects a disease. If you think that’s an idle question, here’s an excerpt from Sue Halpern’s Dec. 22, 2016 review of two books (“Weapons of Math Destruction: How Big Data Increases Inequality and Threatens Democracy” by Cathy O’Neil and “Virtual Competition: The Promise and Perils of the Algorithm-Driven Economy” by Ariel Ezrachi and Maurice E. Stucke) for the New York Times Review of Books,

We give our data away. We give it away in drips and drops, not thinking that data brokers will collect it and sell it, let alone that it will be used against us. There are now private, unregulated DNA databases culled, in part, from DNA samples people supply to genealogical websites in pursuit of their ancestry. These samples are available online to be compared with crime scene DNA without a warrant or court order. (Police are also amassing their own DNA databases by swabbing cheeks during routine stops.) In the estimation of the Electronic Frontier Foundation, this will make it more likely that people will be implicated in crimes they did not commit.

Or consider the data from fitness trackers, like Fitbit. As reported in The Intercept:

During a 2013 FTC panel on “Connected Health and Fitness,” University of Colorado law professor Scott Peppet said, “I can paint an incredibly detailed and rich picture of who you are based on your Fitbit data,” adding, “That data is so high quality that I can do things like price insurance premiums or I could probably evaluate your credit score incredibly accurately.”

Halpern’s piece is well worth reading in its entirety.

Ginger-derived nano-lipids for colorectal cancer

Didier Merlin’s team at the US Dept. of Veteran’s Affairs along with researchers from Georgia State University and from two Chinese universities have published more research on what they are calling, GDNPs, or ginger-derived nanoparticles. (See my Sept. 8, 2016 posting for my first post about ginger nanoparticles and the US Dept. of Veterans Affairs.)

Ginger, well known for relieving nausea, may soon be able to claim another health benefit according to a Sept. 6, 2016 news item on ScienceDaily,

Edible ginger-derived nano-lipids created from a specific population of ginger nanoparticles show promise for effectively targeting and delivering chemotherapeutic drugs used to treat colon cancer, according to a study by researchers at the Institute for Biomedical Sciences at Georgia State University, the Atlanta Veterans Affairs Medical Center and Wenzhou Medical University and Southwest University in China.

A Sept. 6, 2016 Georgia State University news release (also on EurekAlert), which originated the news item, describes both the situation with colorectal cancer in the US and the research,

Colorectal cancer is the third most common cancer among men and women in the United States, and the second-leading cause of cancer-related deaths among men and women worldwide. The incidence of colorectal cancer has increased over the last few years, with about one million new cases diagnosed annually. Non-targeted chemotherapy is the most common therapeutic strategy available for colon cancer patients, but this treatment method is unable to distinguish between cancerous and healthy cells, leading to poor therapeutic effects on tumor cells and severe toxic side effects on healthy cells. Enabling chemotherapeutic drugs to target cancer cells would be a major development in the treatment of colon cancer.

In this study, the researchers isolated a specific nanoparticle population from edible ginger (GDNP 2) and reassembled their lipids, naturally occurring molecules that include fats, to form ginger-derived nano-lipids, also known as nanovectors. To achieve accurate targeting of tumor tissues, the researchers modified the nanovectors with folic acid to create FA-modified nanovectors (FA nanovectors). Folic acid shows high-affinity binding to the folate receptors that are highly expressed on many tumors and almost undetectable on non-tumor cells.

The FA nanovectors were tested as a delivery platform for doxorubicin, a chemotherapeutic drug used to treat colon cancer. The researchers found that doxorubicin was efficiently loaded into the FA nanovectors, and the FA nanovectors were efficiently taken up by colon cancer cells, exhibited excellent biocompatibility and successfully inhibited tumor growth. Compared to a commercially available option for delivering doxorubicin, the FA nanovectors released the drug more rapidly in an acidic pH that resembled the tumor environment, suggesting this delivery strategy could decrease the severe side effects of doxorubicin. These findings were published in the journal Molecular Therapy.

“Our results show that FA nanovectors made of edible ginger-derived lipids could shift the current paradigm of drug delivery away from artificially synthesized nanoparticles toward the use of nature-derived nanovectors from edible plants,” said Dr. Didier Merlin, a professor in the Institute for Biomedical Sciences at Georgia State and a Research Career Scientist at the VA Medical Center. “Because they are nontoxic and can be produced on a large scale, FA nanovectors derived from edible plants could represent one of the safest targeted therapeutic delivery platforms.”

Here’s a link to and a citation for the paper,

Edible Ginger-derived Nano-lipids Loaded with Doxorubicin as a Novel Drug-delivery Approach for Colon Cancer Therapy by Mingzhen Zhang, Bo Xiao, Huan Wang, Moon Kwon Han, Zhan Zhang, Emilie Viennois, Changlong Xu, and Didier Merlin. Molecular Therapy (2016); doi:10.1038/mt.2016.159 Advance online publication 13 September 2016

This paper is behind a paywall.