Ramazzini Institute

Bentivoglio, Italy

Ramazzini Institute

Bentivoglio, Italy

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Background: Breast cancer is the most common cause of cancer death among women worldwide and the second leading cause of tumor-related death for women in westernized countries. Most research efforts to find a breast cancer biomarker have focused on the stage after the cancer is diagnosed. To investigate more deeply into mammary cancer prevention, a study of precancerous lesion development seems a priority. Experimentally-induced mammary tumors in rats constitute a powerful tool for studying the pathogenesis of this cancer and the molecular mechanisms involved in neoplastic progression. Furthermore, in vivo experimental animal models provide information not otherwise available in human populations. 7,12-dimethylbenz[a] anthracene (DMBA) induced rat mammary carcinomas have several similarities with human breast cancers including: histopathology, origination in the ductal epithelial cells, and hormone dependence. To better understand the molecular events associated with mammary carcinogenesis, we used a time-course high throughput gene expression approach on a DMBA-induced mammary cancer model to identify the early precancerous events as well as new potential diagnostic biomarkers. Materials and Methods: Twelve 7 wk-old virgin female Sprague-Dawley rats were randomized into 2 experimental groups: 1) DMBA-treated (40 mg/ kg b.w. by intragastric administration (i.g.) in corn oil as the vehicle and 2) treated with corn oil (vehicle) by ig. At 2 and 4 weeks after DMBA administration, 3 animals randomly chosen from each experimental group were sacrificed and necropsied. Total RNA was extracted and the global gene expression patterns from the mammary gland and liver samples collected were used to identify the molecular profile of the precancerous stage genome. Significantly altered genes as evinced by multivariate data analysis were further confirmed by quantitative real time PCR and siRNA knockdown assays. Results and Discussion: Genes involved in cancer progression, migration, proliferation and oxidative stress were identified in this study. MARK, Wnt and Jak-STAT pathway signaling, known to play a major role at the precancerous stage, were also identified. Two novel less known cancer progression/proliferation related genes, Pcbd1 and Ppil1, upregulated in both liver and mammary glands, were also identified. © Mattioli 1885.


News Article | May 11, 2017
Site: www.beveragedaily.com

Published in the EFSA Journal, the findings are a direct response to allegations made by Italian researcher Morando Soffritti of the Ramazzini Institute. The Institute’s trials with mice were suggestive of sucralose’s harmful effects but its results were largely dismissed by the food industry , critical of its study design and methodology. EFSA concluded that "the available data did not support the conclusions of the authors,” agreeing that the researchers used an unconventional design resulting in inconclusive, unreliable data. The Panel also noted the lack of a mode of action and failure to meet considerations for a cause–effect relationship between sucralose intake and tumour development. Moreover, there was no reliable evidence of in vivo genotoxicity. The International Sweeteners Association’s (ISA) chairman Robert Peterson welcomed the findings commenting that “this scientific opinion from EFSA is entirely consistent with the global scientific and regulatory consensus that sucralose is safe.” The association added that sucralose can be a useful tool, when used in place of sugar and as part of a balanced diet, in helping reduce overall sugar and calorie intake, as well as manage blood glucose levels. “Low calorie sweeteners are also non-cariogenic, which means that they do not contribute to tooth decay.” Scrutiny of sucralose stretches back to 1989, when EFSA first conducted a safety assessment of the sweetener. This was followed up in 2000, where an acceptable daily intake (ADI) of 15 milligrams per kilogram of body weight mg/kg was set. Fast forward to the end of 2015, where EFSA decided to expand the sweetener’s use in foods for special medical purposes for children. Sucralose, listed as E 955 in Europe, is around 600 times sweeter than sugar that is used in over 4,500 food, beverage and pharmaceutical products around the world. In 2011, sucralose accounted for 27.9% of the global sweetener market worth €1.015 billion ($1.146 bn), according to Leatherhead Food Research. “Statement on the validity of the conclusions of a mouse carcinogenicity study on sucralose (E 955) performed by the Ramazzini Institute.”


CARMEL, IN (May 8, 2017) - The European Food Safety Authority (EFSA) decision upholds years of research on sucralose - the sweetening ingredient in the original SPLENDA® Sweeteners - that shows it to be safe and does not cause cancer. The decision was published as an open access Scientific Opinion in EFSA Journal1, and rejects allegations made by a small Italian lab regarding a study in mice that they conducted. EFSA concluded that "the available data did not support the conclusions of the authors (Soffritti et al., 2016)2." EFSA noted numerous issues with the Ramazzini Institute study on sucralose, including: Ramazzini Institute has been criticized previously by the regulatory and research community for not complying with recognized research standards in its sweetener studies. The U.S. Congressional House Committee has also expressed concerns that funding of this lab may not meet adequate scientific integrity standards. The recent EFSA opinion further reinforces the importance of considering recommended research standards when reviewing scientific studies and their results, particularly when the research, as in the case of this latest Ramazzini study, utilizes unconventional methodology and employs scientific practices that have already been found to be problematic for data interpretation. It's important to remember, for food ingredients, industry does not set the guidelines for what type of research must be done. These are set by health and safety research authorities from around the world. The safety of sucralose has been demonstrated by a wide body of research. FDA and other regulatory agencies reviewed more than 110 scientific studies designed to meet the recommended research programs set by expert health authorities for investigating the safety of a new food ingredient. Reviews of these studies have led to consistent conclusions that sucralose is safe, including for women who are pregnant or nursing and for children. SPLENDA® Sweeteners are a safe choice. The science EFSA just dismissed has been used by some, such as the Center for Science in the Public Interest (CSPI), to put sweeteners on their "avoid" lists. As EFSA's review confirms, this is not warranted and is particularly bad counsel when it comes to sucralose-sweeteners like SPLENDA®. SPLENDA® is one way consumers can safely reduce their added sugar and calorie consumption, which we know is important to long-term health. It would be prudent for CSPI to reconsider their advice based on the latest science and determinations from leading food safety authorities. EFSA's decision puts good science first, and it is consistent with the movement to bring greater scrutiny to poorly designed studies that draw false conclusions and unjustifiably alarm consumers. This is a topic we are particularly passionate about at SPLENDA®. We invite others to commit to evaluating research using rigorous scientific judgment and apply sound research findings before making recommendations or sharing opinions. We invite people to learn more about the safety of sucralose. A review of the regulatory and scientific rationale in determining the potential for sucralose to cause cancer is available here. Overconsumption of added sugar is a rising health concern, and low calorie sweeteners like SPLENDA® No Calorie Sweetener help millions of people every day lower their added sugar intake for healthier eating without sacrificing the sweet moments in life. We support people in taking small steps to live a little healthier each day - whether that means cutting back on empty calories, managing weight, staying active and more. For information on how to make simple changes for a healthier you, visit Splenda.com. For more information on EFSA's review of the Ramazzini Institute study of sucralose, visit the report in the EFSA Journal. Based outside of Indianapolis, Heartland Food Products Group is a global leader in the production of low-calorie sweetener products, creamers, beverage concentrates, coffee, and nutritional drinks. Visit Heartland at http://www. . The SPLENDA® Brand is the most recognizable and iconic low calorie sweetener ("LCS") brand in the world, having sold more than 100 billion yellow packets since its launch in 1991. Today, the SPLENDA® Brand is the clear #1 LCS brand in the $72 billion global sweetener market with market shares that are more than twice those of its nearest competitor. Since the acquisition of the SPLENDA® Brand in 2015, Heartland Food Products Group has launched SPLENDA ZERO™ Liquid Sweetener and now SPLENDA® Naturals Stevia Sweetener, expected to be the greatest innovation in the brand's history. 1. EFSA ANS Panel (EFSA Panel on Food Additives and Nutrient Sources added to Food) et al. (2017). Statement on the validity of the conclusions of a mouse carcinogenicity study on sucralose (E 955) performed by the Ramazzini Institute. EFSA Journal 2017;15(5):4784, 14 pp. https:/ 2. Soffritti, M., et al. (2016). Sucralose administered in feed, beginning prenatally through lifespan, induces hematopoietic neoplasias in male swiss mice. Int J Occup Env Health, 22, 7-17 http://dx. .


Artificially sweetened beverages like diet soda are strategically positioned in the market to provide a healthful alternative to sugar-sweetened drinks, which are traditionally linked to a greater risk for conditions such as heart disease, obesity, and diabetes. A new study, however, links diet soda to an increased risk for stroke and dementia, adding to the growing list of health perils associated with the beverages. According to the new research published in the journal Stroke, people who drank at least one diet soda every day maintained nearly three times the risk of suffering from stroke or dementia. The findings were based on 4,300 subjects of the Framingham Heart Study. Over the next decade, subjects who consumed one artificially sweetened soft drink each day had almost three times the risk of having ischemic stroke - the condition when an artery to the brain becomes blocked -compared to those who never drank these soda products. At least one diet soda a day, too, translated to 2.89 times greater risk of developing Alzheimer’s disease, the most prevalent form of dementia that is characterized by memory and cognitive skill decline. "We know that sugary and artificially sweetened beverages are not great for us. This study adds strength to that, and also says they may not be great for your brain, specifically," said Heather Snyder, Alzheimer’s Association senior director in a CNN report. Snyder pointed to alternatives such as cardiovascular fitness to elevate heart rate and enhance blood flow, as well as mental games and puzzles to keep challenging the mind. A 2016 study warned that babies born to mothers consuming diet soda while pregnant were at a greater risk of developing childhood obesity. According to researchers from the University of Manitoba in Canada, pregnant women consuming artificially sweetened liquids every day predispose their children to a higher body mass index during childhood. Of the 3,033 pregnant subjects included in the study, the team saw that 29.5 percent drank these diet drinks while 5.1 percent of kids born to them became overweight by their first year. "To our knowledge, our results provide the first human evidence that artificial sweetener consumption during pregnancy may increase the risk of early childhood overweight," concluded the authors. Diet soda contains high levels of artificial sweeteners, including a form known as aspartame. Early this year, a study argued that there exists no evidence that artificially sweetened drinks are better options for staying slim than sugar-laden versions. Diet drinks are deemed unable to slash the risk for obesity-related diseases, including type 2 diabetes. Experts even raise a red flag: Diet drinks can actually cause one to gain weight, mainly through stimulating one’s sweet cravings and leading one to overeat. Aspartame is low-calorie yet up to 200 times sweeter than regular sugar. It is used worldwide as a sugar substitute in cereals, chewing gum, soft drinks, and thousands of other food and drinks, yet it is not immune to controversy. Reports linked aspartame to a greater chance of brain tumors and cancer, premature birth, allergies, and liver damage. Artificial sweetener sucralose, marketed under the brand name Splenda, had also been tied to a significantly increased risk of leukemia and other cancers. In 2013, it was downgraded from a "safe" to "caution" standing because of earlier research also from the Ramazzini Institute. © 2017 Tech Times, All rights reserved. Do not reproduce without permission.


Mandrioli D.,Ramazzini Institute
Environmental Health Perspectives | Year: 2016

Background: The most essential goal of medicine and public health is to prevent harm (primum non nocere). This goal is only fully achieved with primary prevention, which requires us to identify and prevent harms prior to human exposure through research and testing that does not involve human subjects. For that reason, public health policies place considerable reliance on nonhuman toxicological studies. However, toxicology as a field has often not produced efficient and timely evidence for decision making in public health. In response to this, the U.S. National Research Council called for the adoption of evidence-based methods and systematic reviews in regulatory decision making. The U.S. Environmental Protection Agency (EPA), the Food and Drug Administration (FDA), and the European Food Safety Agency (EFSA) have recently endorsed these methods in their assessments of safety and risk. Objectives: In this commentary we summarize challenges and problems in current practices in toxicology as applied to decision making. We compare these practices with the principles and methods utilized in evidence-based medicine and health care, with emphasis on the record of the Cochrane Collaboration. Discussion: We propose a stepwise strategy to support the development, validation, and application of evidence-based toxicology (EBT). We discuss current progresses in this field produced by the Office of Health Assessment and Translation (OHAT) of the National Toxicology Program and the Navigation Guide works. We propose that adherence to the Cochrane principles is a fundamental prerequisite for the development and implementation of EBT. Conclusion: The adoption of evidence-based principles and methods will enhance the validity, transparency, efficiency, and acceptance of toxicological evidence, with benefits in terms of reducing delays and costs for all stakeholders (researchers, consumers, regulators, and industry). © 2015, Public Health Services, US Dept of Health and Human Services. All rights reserved.


Mandrioli D.,Ramazzini Institute | Belpoggi F.,Ramazzini Institute | Perry M.J.,George Washington University
Environmental Health: A Global Access Science Source | Year: 2016

Aneuploidy, defined as structural and numerical aberrations of chromosomes, continues to draw attention as an informative effect biomarker for carcinogens and male reproductive toxicants. It has been well documented that aneuploidy is a hallmark of cancer. Aneuploidies in oocytes and spermatozoa contribute to infertility, pregnancy loss and a number of congenital abnormalities, and sperm aneuploidy is associated with testicular cancer. It is striking that several carcinogens induce aneuploidy in somatic cells, and also adversely affect the chromosome compliment of germ cells. In this paper we review 1) the contributions of aneuploidy to cancer, infertility, and developmental abnormalities; 2) techniques for assessing aneuploidy in precancerous and malignant lesions and in sperm; and 3) the utility of aneuploidy as a biomarker for integrated chemical assessments of carcinogenicity, and reproductive and developmental toxicity. © 2016 The Author(s).


Background Artificially sweetened beverage consumption has steadily increased in the last 40 years. Several reviews examining the effects of artificially sweetened beverages on weight outcomes have discrepancies in their results and conclusions. Objectives To determine whether risk of bias, results, and conclusions of reviews of effects of artificially sweetened beverage consumption on weight outcomes differ depending on review sponsorship and authors' financial conflicts of interest. Methods We performed a systematic review of reviews of the effects of artificially sweetened beverages on weight. Two assessors independently screened articles for inclusion, extracted data, and assessed risks of bias. We compared risk of bias, results and conclusions of reviews by different industry sponsors, authors' financial conflict of interest and journal sponsor. We also report the concordance between review results and conclusions. Results Artificial sweetener industry sponsored reviews were more likely to have favorable results (3/4) than non-industry sponsored reviews (1/23), RR: 17.25 (95% CI: 2.34 to 127.29), as well as favorable conclusions (4/4 vs. 15/23), RR: 1.52 (95% CI: 1.14 to 2.06). All reviews funded by competitor industries reported unfavorable conclusions (4/4). In 42% of the reviews (13/31), authors' financial conflicts of interest were not disclosed. Reviews performed by authors that had a financial conflict of interest with the food industry (disclosed in the article or not) were more likely to have favorable conclusions (18/22) than reviews performed by authors without conflicts of interest (4/9), RR: 7.36 (95% CI: 1.15 to 47.22). Risk of bias was similar and high in most of the reviews. Conclusions Review sponsorship and authors' financial conflicts of interest introduced bias affecting the outcomes of reviews of artificially sweetened beverage effects on weight that could not be explained by other sources of bias. © 2016 Mandrioli et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


Soffritti M.,Ramazzini Institute | Falcioni L.,Ramazzini Institute | Bua L.,Ramazzini Institute | Tibaldi E.,Ramazzini Institute | And 2 more authors.
American Journal of Industrial Medicine | Year: 2013

Background: More than 10 years have passed since the terrorist attack on the New York City World Trade Center on September 11, 2001. It is well known that long-term carcinogenic bioassays on rodents can predict the potential carcinogenic effects of chemical and physical agents for humans. Objective: A life-span carcinogenicity bioassay was conducted on Sprague-Dawley rats at the CMCRC of the Ramazzini Institute to test the potential carcinogenic effects of settled dust collected at the WTC immediately after the terrorist attack. Methods: The WTC material tested is a complex mixture of coarse particles (95%) contain pulverized cement, glass fibres, asbestos, lead, polycyclic aromatic hydrocarbons (PAHS), polychlorinated biphenyls (PCBS) and polychlorinated furans, and dioxin. The test matter was suspended in sterile saline and administered by intratracheal instillation (IT) to 8-week-old Sprague-Dawley rats (100 animals/sex), 3-4 days/week for 4 weeks. A group of 200 male and female rats served as controls. The animals were kept under observation until natural death. Results: Histopathological evaluation of the lungs (target organ) of instilled control and treated male and female rats, did not show any significant increased incidence of lung tumors. Two hemangiomas (one with endothelial atypia) and one hemangiosarcoma were found in the lungs of treated males. Moreover a modest increased incidence of terminal bronchiolar hyperplasia (TBH) and squamous metaplasia occurred in the lung of treated males and females compared to the controls. Conclusion: Hemangioma and hemangiosarcoma are extremely rare tumors in the lung of our colony and we believe they are caused by WTC dust. © 2012 Wiley Periodicals, Inc.


Soffritti M.,Ramazzini Institute | Belpoggi F.,Ramazzini Institute | Manservigi M.,Ramazzini Institute | Tibaldi E.,Ramazzini Institute | And 3 more authors.
American Journal of Industrial Medicine | Year: 2010

Aspartame (APM) is a well-known intense artificial sweetener used in more than 6,000 products. Among the major users of aspartame are children and women of childbearing age. In previous lifespan experiments conducted on Sprague-Dawley rats we have shown that APM is a carcinogenic agent in multiple sites and that its effects are increased when exposure starts from prenatal life.Objective: The aim of this study is to evaluate the potential of APM to induce carcinogenic effects in mice.Methods: Six groups of 62-122 male and female Swiss mice were treated with APM in feed at doses of 32,000, 16,000, 8,000, 2,000, or 0 ppm from prenatal life (12 days of gestation) until death. At death each animal underwent complete necropsy and all tissues and organs of all animals in the experiment were microscopically examined.Results: APM in our experimental conditions induces in males a significant dose-related increased incidence of hepatocellular carcinomas (P < 0.01), and a significant increase at the dose levels of 32,000 ppm (P < 0.01) and 16,000 ppm (P < 0.05). Moreover, the results show a significant dose-related increased incidence of alveolar/bronchiolar carcinomas in males (P < 0.05), and a significant increase at 32,000 ppm (P < 0.05).Conclusions: The results of the present study confirm that APM is a carcinogenic agent in multiple sites in rodents, and that this effect is induced in two species, rats (males and females) and mice (males). No carcinogenic effects were observed in female mice. © 2010 Wiley-Liss, Inc.


Soffritti M.,Ramazzini Institute | Padovani M.,Ramazzini Institute | Tibaldi E.,Ramazzini Institute | Falcioni L.,Ramazzini Institute | And 2 more authors.
American Journal of Industrial Medicine | Year: 2014

Aspartame (APM) is an artificial sweetener used since the 1980s, now present in >6,000 products, including over 500 pharmaceuticals. Since its discovery in 1965, and its first approval by the US Food and Drugs Administration (FDA) in 1981, the safety of APM, and in particular its carcinogenicity potential, has been controversial. The present commentary reviews the adequacy of the design and conduct of carcinogenicity bioassays on rodents submitted by G.D. Searle, in the 1970s, to the FDA for market approval. We also review how experimental and epidemiological data on the carcinogenic risks of APM, that became available in 2005 motivated the European Commission (EC) to call the European Food and Safety Authority (EFSA) for urgent re-examination of the available scientific documentation (including the Searle studies). The EC has further requested that, if the results of the evaluation should suggest carcinogenicity, major changes must be made to the current APM specific regulations. Taken together, the studies performed by G.D. Searle in the 1970s and other chronic bioassays do not provide adequate scientific support for APM safety. In contrast, recent results of life-span carcinogenicity bioassays on rats and mice published in peer-reviewed journals, and a prospective epidemiological study, provide consistent evidence of APM's carcinogenic potential. On the basis of the evidence of the potential carcinogenic effects of APM herein reported, a re-evaluation of the current position of international regulatory agencies must be considered an urgent matter of public health. Am. J. Ind. Med. 57:383-397, 2014. © 2014 Wiley Periodicals, Inc.

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