A case study in risk assessment: aspartame Herman B.W.M.Koëter Managing Director,, Brussels, Belgium Thanks to Dr Iona Pratt of the Irish Food Safety Authority for use of a number of the slides in this presentation
Apartame the most hated food additive of all time! MY ASPARTAME EXPERIMENT A FEMALE RAT DEVELOPED A MAMMARY TUMOR SO LARGE SHE OFTEN USED IT AS A PILLOW BY VICTORIA INNESS-BROWN, M.A. I WANTED VISUAL PROOF I did my aspartame experiment because my family was addicted to diet soda. After researching the effects of aspartame, I strongly believed the artificial sweetener might one day lead to their illness and even early death.. Welcome to ASPARTAMEKILLS.C OM If you were told that Aspartame was synthesized by fermenting protein in GENETICALLY MODIFIED E-COLI Bacteria, would you consume it? Check out Jeffrey Smith's Lecture at Weston Price Everything You HAVE TO KNOW about Dangerous Genetically Modified Foods from Jeffrey Smith on Vimeo. 2
Aspartame (E951, Nutrasweet, Aminosweet) Used as sweetener in foods and as a table-top sweetener; In use for more than 20 years in many countries; same calorific value as sugar, but about 200 times sweeter than sugar; methyl ester of the dipeptide of two amino acids, phenylalanine and aspartic acid; 3
Background Originally approved for use by US FDA 1981-83 ADI of 40mg/kg established by JECFA (1980) SCF in 1985, 1989, 1997, and 2002 EFSA, 2006, 2009, 2011 2-3 April National Experts on Aspartame 4
Issues Required studies on aspartame were done in the 1970 s pre-glp, some controversy about how they were done, their adequacy Nonetheless, judged by regulatory agencies as providing evidence for safety of aspartame Key issue: aspartame is hydrolysed in the gut to its constituent amino acids (aspartate and phenylalanine) and methanol All normal constituents of food and the human body 5
Issues Continued controversy about the approval process; Health/toxicological issues brain tumours in some test animals in the 1973 chronic toxicity/carcinogenicity study in rats, not seen in other studies; alleged connection between aspartame and an increase in incidence of brain tumours in humans in the USA during the 1980s; Reports of neurological disturbances in humans (headaches, dizziness, mood changes, association with ME, MS, Gulf War Syndrome, etc) 6
Aspartame: a case study Is aspartame safe for its intended use? Should it be withdrawn from the market? Could this sweetener be carcinogenic or have the other effects attributed to it? 7
Assumed neurological effects of aspartame Continues to be of concern complaints from individuals public interest groups (e.g. Mission Possible, Dr Betty Martini) 2-3 April National Experts on Aspartame 8
Carcinogenicity New studies questioning safety: Soffritti et al.(2005) Ramazzini Institute (Italy) Authors reported an increased incidence of malignant tumours in animals given aspartame Belpoggi, Soffritti et al. (2006) Reported statistically significant increase in lymphomas and leukemias in females given aspartame, at levels similar to the current ADI Soffritti et al., 2010 Reports that aspartame induces cancer in the livers and lungs of male Swiss mice, supporting their previous conclusions that aspartame is a carcinogenic agent in rodents 2-3 April National Experts on Aspartame 9
DESIGN OF THE 1 ST RAMAZZINI STUDY Male and female rats 100-150 animals/sex/dose group Treated from 8 weeks of age until natural death 6 dose groups plus controls Doses: 80 100,000 mg aspartame per kg diet Intakes of aspartame ranged from approximately 5-5000 mg/kg bw/day (>100x ADI)
RAMAZZINI S INTERPRETATION OF THEIR FINDINGS (1) ERF concluded there were increases in: Total number of malignant tumour-bearing animals Lymphomas and leukaemias especially in female rats Carcinomas of the kidney and ureter with precursor lesions (dysplasia) in females Malignant Schwannomas of peripheral nerves
EFSA conclusions, 1 st study A full assessment of the study (histopathology) was not possible because of the histological material could not be accessed; Statistical evaluation was not possible because data were only made available as paper copies; The study design was not in accordance with internationally accepted test methods; There was a high level of background pathology in all groups including controls.
EFSA conclusions, 1 st study (2) Increase in cancers in treated rats was unrelated to aspartame treatment; No dose response relationship with respect to increasing doses of aspartame; Findings in the kidney and bladder were not relevant to humans; Diagnosis of tumours of peripheral nerves (Schwannomas) was uncertain.
EVALUATION BY EFSA FINDINGS REQUIRING FURTHER EVALUATION Malignant Schwannomas of peripheral nerves Dose-related, hyperplastic changes in olfactory tissue These reported findings are difficult to interpret, and the EFSA Panel was unable to draw a definitive conclusion about them.
NEUROLOGICAL EFFECTS OF ASPARTAME Who is right, Betty Martini and the other aspartame activists on the web, Prof Soffritti, or the regulatory authorities? What would you suggest doing to get to the bottom of this? 15
EFSA 2009-2010 review Incorporated information contained in these unverified case reports into a database not previously considered by SCF or JECFA Call for data documents submitted by correspondence opportunity to address EFSA Study in human volunteers 2-3 April National Experts on Aspartame 16
Call for data Articles from health and lifestyle publications Information published on internet: largely anecdotal; Unpublished scientific literature e.g. MSc end papers, PhD theses; Views of individuals; Letters. 2-3 April National Experts on Aspartame 17
Summary data SYMPTOMS % HEADACHE 28.7% DIZZINESS 11.3% CHANGE IN MOOD 10.3% VOMITING NAUSEA 10.2% ABDOMINAL PAIN 7% CHANGE IN VISION 5.7% DIARRHOEA 5.2% 2-3 April National Experts on Aspartame 18
Issues Can this molecule produce these effects? Aspartic acid: an excitation inducing amino acid Phenylalanine of concern in phenylketonuric individuals Methanol?? 19
DESIGN OF THE 2 nd RAMAZZINI STUDY (2006) Male and female rats, 70 animals/sex/dose group (95 in controls) Treated from 12th day of gestation until natural death (in utero exposure) 2 dose groups, receiving approximately 20 or 100 mg/kg bw/day (2.5 times the ADI) plus controls
RAMAZZINI S INTERPRETATION OF THEIR FINDINGS (2 nd study) ERF concluded there were increases in: Total number of malignant tumour-bearing animals (males only) Lymphomas and leukaemias especially in female rats dose-related increase in incidence of mammary carcinomas in females, particularly in the highdose group
EVALUATION BY THE EFSA PANEL DATA REVIEWED BY THE PANEL & ITS WORKING GROUP Looked in detail at the report provided to EFSA by the ERF and its two publications Looked at the limited peer review on selected lesions from the ERF study carried out by the US National Toxicology Program (NTP) Looked at all the available studies on genotoxic potential Looked at NTP studies for detection of cancer in transgenic mice published in 2004 Considered previous evaluations by national and international bodies on the original four cancer tests in rats and mice conducted in the 1970s/early 1980s
EVALUATION BY THE EFSA PANEL CONCLUSION Data on total malignant tumours do not provide evidence of carcinogenic potential REASONING Adding together of all tumours is not justified Especially as some of the tumour types are not relevant for human risk assessment
EVALUATION BY THE EFSA PANEL CONCLUSION Lymphomas and leukaemias are unrelated to the aspartame treatment REASONING High background rate of chronic respiratory disease (likely cause of tumours) Lack of clear positive dose-response (despite very wide dose range)
CONCLUSION EVALUATION BY EFSA increase in incidence of mammary carcinoma is not considered indicative of a carcinogenic potential of aspartame since the incidence of mammary tumours in female rats is rather high and varies considerably between carcinogenicity studies. The Panel also noted that an increased incidence of mammary carcinomas was not reported in the previous ERF study with aspartame which used much higher doses of the compound
OTHER RELEVANT STUDIES The US National Toxicology Program conducted studies for cancer in two strains of transgenic mouse The results did not show any carcinogenic potential (NTP, 2004) The US National Cancer Institute carried out an epidemiological study of aspartame consumption and cancer incidence in over 560,000 people The results showed no association of aspartame consumption with any increased risk for haematopoietic (blood-related) or brain cancers
INTAKES OF ASPARTAME Several studies on intakes of aspartame in Europe, conducted between 1992 and 2001, show similar results Intakes range from around 2-10 mg/kg bw/day, including in high consumers such as diabetics Well below the EU Acceptable Daily Intake of 40 mg/kg bw for aspartame
OVERALL CONCLUSIONS BY EFSA (2009) The EFSA Panel concluded that at present there are no scientifically convincing data from the 2006 Ramazzini carcinogenicity study to indicate the need for any revision of the ADI of 40 mg/kg bw, previously established for aspartame.
Soffritti et al., 2010 mice exposed to aspartame at 242, 987, 1919 and 3909 mg aspartame/kg bw/day from the 12th day of gestation until natural death or for 130 weeks. significant dose-related increase in hepatocellular carcinomas in the 2 top dose groups Increased incidence of alveolar/bronchiolar carcinomas in males at the highest dose group No compound-related carcinogenic effects in female mice at any of the doses tested. 29
EVALUATION BY EFSA hepatic and pulmonary tumour incidences reported by Soffritti et al. fall within their own historical control ranges for spontaneous tumours. Swiss mice are known to have a high background incidence of spontaneous hepatic and pulmonary tumours hepatic tumours in mice are generally considered as irrelevant for human risk assessment
EVALUATION BY EFSA EFSA have concluded that on the basis of the information available in the publication, the validity of the study and its statistical approach cannot be assessed and its results cannot be interpreted. the results do not provide sufficient scientific evidence to reconsider the previous evaluations by EFSA and SCF EFSA noted that Soffritti et al. suggested that the metabolism of aspartame leading to the formation of methanol might have played a role in the development of hepatocellular tumours.
CARCINOGENICITY OF ASPARTAME Who is right, Dr Soffritti or the regulatory authorities? Could aspartame be a carcinogen? What is the carcinogen methanol? What do you think? 32
Issues Can this molecule produce these effects? Methanol??? (metabolised to formaldehyde) no evidence of direct interaction of aspartame with DNA that could indicate carcinogenicity 33
CONCERNS REGARDING STUDIES CARRIED OUT BY RAMAZZINI INSTITUTE GLP status? Positive findings for a number of chemicals e.g. MTBE, methanol, which have tested negative in other laboratories Accuracy of pathological diagnoses? 34
CONCERNS REGARDING STUDIES CARRIED OUT BY RAMAZZINI INSTITUTE EPA Places Four IRIS Assessments on Hold Pending Review (EPA Press Release date: 15/6/2010) WASHINGTON The U.S. Environmental Protection Agency (EPA) announced today that it is holding four of its ongoing IRIS (Integrated Risk Information System) assessments pending a review of some of the underlying studies used in the assessments. 35
CONCERNS REGARDING STUDIES CARRIED OUT BY RAMAZZINI INSTITUTE EPA is holding these assessments due to a report from the National Toxicology Program (NTP) that outlines a recent review of a research study completed by the Ramazzini Institute, a lab in Italy that conducts animal testing to evaluate the potential cancer-causing effects of chemicals. The report discusses findings from a recent assessment by NTP pathologists of an animal study on methanol. NTP s report recommends that further pathology reviews be carried out to resolve differences of opinion between NTP scientists and the Ramazzini Institute in the diagnoses of certain cancers reported in the study. 36
FURTHER STUDY EVALUATED BY EFSA Halldorsson et al. (2010) examined the association between intakes of sugar-sweetened and artificially sweetened soft drinks and preterm delivery in a cohort of 59,334 pregnant women. Authors concluded that the daily intake of artificially sweetened soft drinks may increase the risk of preterm delivery in pregnant women Aspartame implicated
EFSA CONCLUDED: There is an association between intake of artificially sweetened carbonated and noncarbonated soft drinks and an increased risk of preterm delivery No causal relationship can be identified confounders? several sweeteners are used alone or in combination in soft drinks, no justification to focus on any specific sweetener further studies would be needed to reject or confirm the findings. 38
Aspartame: a case study Is aspartame safe? Should it be withdrawn? Could this sweetener be carcinogenic or have the other effects attributed to it? Where are we on the human volunteers study? 39