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(20 pts) According to a recent press release, " A second study conducted by the European Ramazzini Foundation (ERF) at http://www.ramazzini.it/ confirms the carcinogenicity of aspartame". In 2005, the European Ramazzini Foundation published important experimental data demonstrating the carcinogenicity of aspartame. These data demonstrated for the first time that aspartame is a carcinogenic agent, including various types of malignant tumors in rats, even at dose levels currently considered acceptable for humans. Should we be concerned with the consumption of the artificial sweetener aspartame? Explain. Aspartame (APM) is the second most used artificial sweetener in the world. About > 8000 tons of APM are consumed each year in the U.S. In terms of world consumption, APM represents 62% of the value of the intense sweetener (Soffriti et al., 2006) and is currently found in >6,000 food and beverage products . On average daily consumption of aspartame has been estimated to be 2.5-5 mg/kg b.w. The current accepted daily intake (ADI) of APM in the USA and European Community is 50 and 40 mg/kg b.w., respectively (Chiozzotto et al., 2011). Three long-term carcinogenicity studies performed in the 1970s-1980s found aspartame to be safe, which became the basis for FDA to approve the use of APM in foods in 1981. The experiments were done, two on rats and one on mice, by the industry producing APM. (Chiozzotto et al., 2011). Ishii (1981) fed groups of SCL Wistar rats 0, 1, 2 or 4 g/kg aspartame, or 4 gm/kg aspartame and diketopiperazine (DKP) (3:1) for 104 weeks and found no brain tumors in the interim sacrifice animals. Olney et al. (1996), performing a descriptive analysis of national cancer data (increase in incidences of brain tumor rates in 1984-1987, immediately after FDA approval of use of APM) , suggested the possibility that aspartame might be associated with increased incidence of brain tumors in the U.S. They further emphasized the need of reassessment of carcinogenicity of APM. The National Toxicology Program (NTP, 2003a) has conducted non-standard bioassays in both sexes of genetically altered ( haploinsufficent) mice. There was no evidence of treated-related carcinogenicity. A well-conducted epidemiological study (health cohort study) showing no association between cancer and aspartame consumption in humans (Lim et al., 2006) is also available. Soffritti et al. (2006) of the European Ramazzini Foundation of Oncology and Environmental Sciences (ERF) reported that aspartame was associated with an increase in lymphomas and leukemias, transitional cell carcinomas of the renal pelvis and urethra, malignant schwannomas of peripheral nerves, and hyperplasia of the olfactory epithelium. These studies, however, have been criticized by the highly respected regulatory and scientific organisations viz; European Food Safety Authority (EFSA), USFDA, Aspartame Expert Panel Report and the United Kingdom Committee on Carcinogenicity of Chemicals in Food, Consumer Products and the Environment. These organizations criticizes that the Ramazzini Institute researches have multiple, serious problems with experimental design, interpretation of results and data reporting. Independent reviews have been highly critical of these two studies for many valid reasons. No regulatory agency has considered the Ramazzini aspartame studies to be credible evidence of carcinogenicity, and no regulatory agency has ever relied upon the Ramazzini studies of aspartame for regulatory purposes.

2000. Dose Tests Result Conclusions Aspartame Administered in Feed. By these tiresome efforts. 0 ppm Microscopic histopathologi cal studies A significant dose-related increased incidence of hepatocellular carcinomas and increased incidence of This confirms that APM is a carcinogen in multiple sites in rodents and thsat this effect is induced in .Further.. Induces cancer of the Six groups of 62122 male and female swiss 32. Table 1: Summary of animal carcinogenicity studies (adapted from Magnuson et al. 16000.000 . They have tried to address all the criticisms by the regulatory bodies and independent scientists. Title (Year) Animals used Duration of feeding and observati on Prenatal life (12 days of gestation) to natural death. Beginning Prenatally Through Life Span. 8000. Table 2. ERF scientists conducted researches and published their results in 2010 and 2011. 2007) Table 2: Findings of European Ramazzini Foundation of Oncology and Environmental Sciences after the criticism from Regulatory bodies. and consistent findings in their studies ERF scientists again confirms the carcinogenicity of APM.

. FDA seems to be still using the 3 decades old findings to ensure safety of peoples. In one hand the reputable regulatory bodies like FDA. heightened. we should be concerned with the consumption of the artificial sweetener.. Conclusion: Weighing out the two contrasting school of thoughts. 2011) also have answers to all the critical questions raised by the regulatory bodies in 2009. EFSA. No carcinogenic effects were observed in female mice. ERF keeping in mind the criticisms. Also. on the basis of facts in front of us. alveolar/bronchio lar carcinomas in males. 400 or 0 ppm to simula te a daily APM intake of 100.. it tends to alarm us about the dangers of aspartame. lifespan mammary treatments adenocarcinomas stars from in females. They criticized (in 2005 and 2009) the findings of ERF but they never tried to perform the experiment themselves. ERF now ( as from Soffritti et al. Contemplating in this matter. The reluctance of regulatory bodies to prioritize aspartame safety. 20 or 0 mg/kg body weight respec tively. Microscopic A significant This again histopathologi dose-related confirms the cal studies increased carcinogenici incidence of ty of APM in Females bearing rats. (Chiozzotto et al. seems to be unusual and makes us little skeptic. In this serious issue. Thus. rats and mice. about the safety of aspartame is confusing somehow. aspartame. regulatory bodies are not as active as any non-profit research institute like ERF. EC etc are not willing to deal aspartame as high priority whereas on the other hand ERF scientists have proof of potential carcinogenicity of aspartame to humans and are demanding the review of guidelines of use of aspartame in food.. 2010) mice Results of life span carcinogenicit y bioassay on SpragueDawley rats exposed to aspartame since foetal life. aspartame has been proved to carcinogenic in rodents and is potentially so to humans. This fits the definition of carcinogens 'group 2A'. given by International Agency for Research on Cancer (IARC). continued their research and are with the consistent findings. two speciees. The benign tumours.liver and lung in male Swiss mice (Soffritti et al. 2011) 470 Sprague -Dawley rats Foetal life until natural death 2000. data also males bearing show that malignant when the tumours. The scientific bases upon which FDA approved the use of aspartame some 30 years ago needs to be revitalized. foetal life the lymphomas/leuk carcinogenic aemias in males effects are and females. As per the confirmation by ERF scientists.

Consumption of Aspartame-Containing Beverages and Incidence of Hematopoietic and Brain Malignancies. J. M. Falcioni. L. beginning prenatally through life span. and A. and Luciano Bua.N. J. Rigano. M.H. Am..114(3): 379-85. Tibaldi. Doull. Farber. 22839-47-0) in FVB/N-TgN(v-Ha-ras)Led (Tg. Falcioni. induces cancers of the liver and lung in male Swiss mice. 2007). Pariza. Incidence of brain tumors in rats fed aspartame. Burdock. Eur. S. (15pts) Describe the Maillard reaction. Soffritti M.W.F. G. Tibaldi. 03-4459. T. E. U.1981. P. regulations. J.129-Trp53tn1Brd (N5) Haplosufficient Mice (Feed Studies).AC) Hemizygous Mice and Carcinogenicity Studies of Aspartame in B6. F. 56(1):1115-23. Cancer Epidemiology Biomarkers and Prevention. B. Magnuson. M. Public Health Service. Increasing brain tumor rates: is there a link to aspartame? J Neuropath Experimental Neurol. 2010. 2011. Soffritti. . R. Belpoggi. L. F.W. 37:629727.. 1996. Degli Esposti. F.S. G.. NIH Publication No.. Manservigi. Belpoggi. NTP. L. U. J. 6. Olney. A. Lauriola. National Institute of Health. Ishii. et al.. Manservigi. Marsh.B.References: Chiozzotto D. 53: 1197-1206. Oncol.16(2): 81-97. Soffritti M. Walker and G. Aspartame administered in feed. A. E. DRAFT NTP Technical Report on the Toxicity Studies of Aspartame (CAS No. Belpoggi. Results of life span carcinogenicity bioassay on Sprague-Dawley rats exposed to aspartame since foetal life.. Williams. 2007. Subar. 2006. 2003a). Maillard reaction is a browning (non-enzymatic) reactions occuring in thermally processed foods. Bua. Toxicology Lett. E. First experimental demonstration of the multipotential carcinogenic effects of aspartame administered in the feed to Sprague-Dawley rats. Tibaldi. 7:433-437. E. Manservisi. Describe the potential adverse effects and benefits that might be derived from ingesting such products.. Kroes. M. Robins. M. NTP GMM 1. Environ. M. A. Spitznagel and L. J. N. Lim. R. National Toxicology Program (NTP. 15:1654-1659. Med. and toxicological and epidemiological studies. M. The reactants are amino acids and reducing sugars which leads to the formation of a complex series of compounds called Maillard reaction products (MRPs) ( Wagner et al. Waddell . W. Spencer . F. Critical Reviews in Toxicology. M. Mouw. Lambertini. Department of Health and Human Services. D. Health Perspect. Ind. Aspartame: a safety evaluation based on current use levels. L.

The early Maillard reaction A reducing sugar.2-enolisation with the formation of furfural (when pentoses are involved) or hydroxymethylfurfural (HMF). At pH 7 or below. the intermediate product in the Maillard reaction and the degradation of sugars also formed at high temperatures .. 2001) A. the degradation of Amadori compound is thought to . it undergoes mainly 1. 2001). The advanced Maillard reaction The subsequent degradation of Amadori product is dependent on the pH of the system . At pH >7. b. like glucose (as an aldehyde in open chain form).Figure 1: Scheme of Maillard Reaction (adapted from Martins et al. Mechanism of the Maillard reaction a. condenses with a compound possessing a free amino group (of an amino acid or in proteins mainly the ε-amino group of lysine. to the so-called Amadori product (Martins et al.. N-substituted glycosylamine via formation of a Schiff’s base and the Amadori rearrangement. also the α-amino groups of terminal amino acids) to give a condensation product.

aldo clevage at C-3 to C-4. 2007). The compound can react with free glycine and produce more compound that subsequently undergoes a β-elimination to form methylglyoxal and releases glycine (Martins et al. leading to the formation of brown nitrogenous polymers and co-polymers.deoxy-2-hexosulose and 3–deoxy-2. However. 2001). It is expected that lysine residues are involved in melanoidins. such as food safety. MRPs have been shown to have positive effects on gut health due to stimulating effects on health beneficial bacteria. Carbonyl groups can condense with free amino groups. This reaction is known as the Strecker degradation (Martins et al. 2005). All these compounds are highly reactive and take part in further reactions.involve mainly 2. 2001) c. Next to the sensory properties. 2001). or binding gut harmful substances. Another possible mechanism of degradation of Amadori compound involves a retro-aldol reaction. 2-enaminol and 1-amino-1. The degradation of Amadori compound N-(1-deoxy-D-fructose-1-yl)-glycine. pyruvaldehyde and diacetyl. The final Maillard reaction In an advanced stage. retroaldolizations. The degradation of Amadori compound take place through enolosation such as the formation of glucosones by transition-metal catalyzed oxidation of 1. 3-enaminal.. known as melanoidin. a range of reactions including cyclization. 3-hexodiulose. including that generates 1-glycine-1-deoxy-D-glyceraldehyde and glyceradehyde through a retro. from sugar degradation.. Dicarbonyl compounds will react with amino acids with the formation of aldehydes and α-aminoketones. isomerizations and further condensations take place. where reductones. 2001). brown pigments are also formed without nitrogen mainly. which results in the incorporation of nitrogen into the reaction products. respectively. including acetol.. and the nutritional value of foods. The Maillard reaction also has both nutritional and toxicological effects on processed food (Ho. dehydrations. are the main quality criteria of foods (Somoza. it has been noted already for a long time that brown components are mainly bound to protein.. 3-diulose by elimination of C-4 OH group of 2. exhibit antioxidative effects. Beneficial and adverse effects of Maillard reaction products Significant quantities of dietary MRPs and melanoidins enter the human intestines every day. DFG) by 1. Melanoidins are of a high molecular weight (up to about 100. and they contain nitrogen by definition. 2–enolisation and 2. are formed. they are discussed to have effects on chemoprevention and MRPs were shown to influence the glycation reaction ( Wagner et al. health aspects..000). 2006). B. 3-enolisation leads to the formation of 3. the content of health-promoting nutrients. 4-dideoxy-2. rearrangements. a) Beneficial effects Highly depending on the reaction conditions. In the case of milk. because lysine loss also increases during the final stage (Martins et al. The formation of these intermediates is accompanied by amino acid release (Martins et al. but the nature of the bonds is not clear. 3-enolisation. .

effects on enzyme acitvity and effects on the absorption and utilization of metals. Nutr. cts of Maillard reaction products used as “natural antibrowning” agents. 2006). Some scientists also discuss that some melanoidin intermediates can effectively suppress peroxidation. .din mixtures Mutagenic and genotoxic effects Compared to the effects ofwell-known mutagens. Antinutritional aspects includes. 2007. 2005) Health Effects Main Results obtained Effects on gut health Model melanoidin mixtures stimulates the growth of health-beneficial bacteria in the gut. The potential antimutagenic and antioxidant effects of Maillard reaction products used as “natural antibrowning” agents. model melanoidin mixtures shownegligible mutagenic and genotoxic effects in in vitro systems. Mol. Effects on glycation reactions Model melanoidin mixtures aswell as chemically characterized compoundswere demonstrated to bind to the receptor of AGEs (advanced glycation end products) in vitro. Chriot. 51: 496– 504.H. Effects on the chemopreventive potential Induction of chemopreventive enzymes in in vitro and in vivo systems by model and food melanoidin mixtures Effects on the anti. Asparagine-mediated Maillard reaction is known to lead to the formation of neurotoxic acrylamide. effect on the availability of essential amino acids. Koschutnig and S.Table 3: health effects of MRPs and melanoidins (adapted from Somoza. The Maillard reaction is responsible for the formation of potent mutagenic/carcinogenic heterocyclic aromatic amines (HAAs) in heated meat and fish. Increased antioxidant capacity in the plasma of humans after administration of food melanoi. possibly resulting in pro-inflammatory reactions on a cellular level .. S. maillard reactions also pose some negative impacts in health of the consumers. References Wagner. Intake of food melanoidins by healthy vegetarianswas not as. C. Food Res.oxidant capacity Inhibition of lipid peroxidation by model melanoidin mixtures in isolated hepatocytes. scavenging free radicals and prevent oxidative cell injury (Ho. They also bind to HAAs (heterocyclic aromatic amines) and may subsequently decrease the absorption rate of HAAs. K. Billaud.sociated with increased AGE levels in human plasma. b) Harmful effects Many findings suggests apart from the beneficial effects. Reichhold . K.

(Helferich and Winter. packaging. flavoring agents.. S. antioxidants. van Boekel.I. Editorial: Maillard Reaction and Health Aspects. more than 2. Mol. Table 4 lists the most common food additives used for various purposes. The term does not include contaminants or substances added to food for maintaining or improving nutritional qualities (CODEX. 1995) . the intentional addition of which to food for a technological (including organoleptic) purpose in the manufacture.M. and miscellaneous additives.S. 49: 663–672. means any substance not normally consumed as a food by itself and not normally used as a typical ingredient of the food.F. Five years of research on health risks and benefits of Maillard reaction products: An update. T. Today. bleaching agents. 2005. Ho. treatment. 2001. W. Trends in Food Science & Technology. V. texturizing agents. preparation. or may be reasonably expected to result (directly or indirectly). Substances intentionally added to foods vary from preservatives to flavoring materials. Nutr. Nutr.F. Somoza. whether or not it has nutritive value. 50: 1099–1100 . Mol. Table 4: Types and properties of some intentional foods additives (adapted from Maga.Martins. sweeteners. A review of Maillard reaction in food and implications to kinetic modelling.J. They include preservatives. C. packing. 2006. in it or its byproducts becoming a component of or otherwise affecting the characteristics of such foods. transport or holding of such food results. Food Res. Food Res. Intentional food additives.11: 364–373.500 different additives are intentionally added to produce desired effects. Provide a few examples of each and describe how incidental additives get into foods and why intentional additives (function of additives) are added to foods. 5. nutritional additives. processing. Jongen and M. coloring agents. (15 pts) Distinguish between intentional and incidental food additives.S. 1995). 2001).

storage. W. 2012. does not mislead the consumer. Types of food additives. . As for example the permitted agricultural chemicals used on farm products or accepted drugs and nutrients fed to animals. Boca Raton: CRC Press. and A. b) To provide necessary ingredients or constituents for foods manufactured for groups of consumers having special dietary needs. New York. Maga. and serves one or more of the technological functions set out by Codex and the needs set out from (a) through (d) below. even when used according to good husbandry practices. Most of the incidental additives are the substances permitted to be used in any stages of production of a particular product. or packaging.. J. and the amount carried over into the food does not exceed that expected by good manufacturing practice. 1995. An incidental additive could be a substance present in food due to migration or transfer from the package or processing equipment.pdf. treatment. transport or storage of food. preparation. (Helferich and Winter. incidental additives are not allowed in infant and children foods. does not present an appreciable health risk to consumers.net/gsfaonline/docs/CXS_192e. which "may reasonably be expected to become a component of food. Maga. d) To provide aids in the manufacture. processing. and packaging. Animal drug residues and food contact substances. Some 10. processing. (Helferich and Winter. an intentional reduction in the nutritional quality of a food would be justified in the circumstances dealt with in sub-paragraph (b) and also in other circumstances where the food does not constitute a significant item in a normal diet. (CODEX. substance or quality of the food so as to deceive the consumer. packing. J. (CODEX. 2001. September 27. CODEX GENERAL STANDARD FOR FOOD ADDITIVES CODEX STAN 192-1995.T. may end up in the food supply. and only where these objectives cannot be achieved by other means that are economically and technologically practicable: a) To preserve the nutritional quality of the food. Winter. Marcel Dekker Inc. 1995.Additives of the second type are incidental and may be present in finished food in trace quantities that are harmless to consumers and are present as a result of some phase of production. 1. Available Source: http://www. 2001) Codex describes the incorporation of incidental or unintentional food additives is mainly due to the principle of "carry-over". Such agricultural chemicals. Food toxicology. 1995) References CODEX.000 substances make their way into food during growing. provided that the additive is not used to disguise the effects of the use of faulty raw materials or of undesirable (including unhygienic) practices or techniques during the course of any of these activities. However.A. processing. Tu. the amount in the raw material does not exceed the maximum amount so permitted in the raw material or ingredient. Eds. A." must be shown to be safe for humans under similar standards as food additives. provided that this does not change the nature. The most important thing to be noted is that. Helferich. 2001) Food residues from pesticides and drugs also belong to this category. or additives used as a component in ingredients may turn up in trace amounts in finished food products.codexalimentarius. such substances are permitted only if the substance was permitted in the raw material or ingredient initially. K. in Food Additive Toxicology. 1995) Purpose of addition of intentional additives to foods: The use of food additives is justified only when such use has an advantage. c) To enhance the keeping quality or stability of a food or to improve its organoleptic properties. and C.. some of these accidental additives can pose more of a health threat than preservatives and other direct additives.

1958 ) a petitioner. 2009. (D) a description of practicable methods of determining the quantity of such additive in or on food. within 15 days. petitions filed shall include that the study contained in the petition has been. must provide. or was not subject to such requirements in accordance with 21 CFR 56. When an additive is proposed for use in a meat or poultry. government to have these additives approved for use in meat and poultry products. According to Code of Federal regulations (under the provision of FFDCA Section 409(b)(2). poultry. including all directions.S. 2009. If non clinical laboratory studies are involved. (30pts) You are working for a research company that have both a "natural" and "synthetic" food additive that have been shown to have potential as antioxidants and antimicrobials in meat and poultry products. and suggestions proposed for the use of such additive.C. where available. and any substance formed in or on food. and egg products. Please answer the following questions (exception: you can answer up to 2000 words for this question): a) Find and review the USDA/FSIS and FDA regulations to determine what requirements are needed to petition the government for use of new food additives. Furthermore. whether use of the substance would be permitted in products under USDA jurisdiction under specified conditions or restrictions. If clinical investigations involving human subjects are involved. and the quantity of the additive required to produce such effect. 2009. forward a copy of the petition or relevant portions thereof to the Food Safety and Inspection Service. A petition for a food additive is submitted to request issuance of a regulation allowing new uses of the additive and must contain the necessary supporting data and information. Department of Agriculture (USDA) under the Poultry Products Inspection Act (PPIA) (21 U. 451 et seq. (B) a statement of the conditions of proposed use of such additive. So these products are subject to regulation by the U. or if not.) or the Federal Meat Inspection Act (FMIA) (21 U. including full information as to the methods and controls used in conducting such investigations and (F) include a proposed regulation (21 CFR 171. in addition to any explanatory or supporting data: “(A) the name and all pertinent information concerning such food additive. and .S. including. FDA shall. petitions filed shall include statements regarding each such clinical investigation relied upon the petition that it either was conducted in compliance with the requirements for institutional review set forth in part 56 of 21 CFR. and including samples of its proposed labeling.5. and that it was conducted in compliance with the requirements for informed consent set forth in part 50 of 21 CFR. recommendations.105.). (E) full reports of investigations made with respect to the safety of such additive. for simultaneous review under the PPIA and FMIA. Discuss the government procedures and what information is needed for both natural and synthetic additives. because of its use. requesting the issuance of a food additive regulation. 601 et seq. conducted in compliance with the good laboratory practice regulations. 2009).S. or will be. Department of Agriculture (USDA) shares responsibility with FDA for the safety of food additives used in meat. After receipt of the petition. (C) all relevant data bearing on the physical or other technical effect such additive is intended to produce. its safety. its chemical identity and composition. technical function. the the petition must be signed by an authorized official and the information provided must be complete as per required by FFDCA Section 409(b). The Food Safety and Inspection Service (FSIS) of the U. FDA will ask USDA to advise whether the proposed meat and poultry uses comply with the FMIA and PPIA. Your company would like to petition the U.S.1. USDA.S. List and include the information from the Code of Federal Regulations. upon filing of the petition.104 or 56. The intended use of the proposed food additive include uses in meat and poultry. FDA will notify the petitioner of the acceptance or non cceptance of a petition.C.

and prior to the forwarding of the order to the FEDERAL REGISTER for publication shall notify the petitioner of such order and the reasons for such action. or by order deny the petition. and shall notify the petitioner of such order and of the reasons for such action. chemistry.C. Information needed for both natural and synthetic food additives: a) The identity and composition of the additive b) Proposed use c) Use level d) Data establishing the intended effect e) Quantitative detection methods f) Estimated exposure from the proposed use (in food. drugs. and ๔.C. specifications as to the particular food or classes of food in or on which such additive may be used. meat food product. he shall by written notice to the petitioner extend the 90-day period for not more than 180 days after the filing of the petition. toxicology.. FDA and FSIS continually review the safety of approved additives.S. to determine if approvals should be modified or withdrawn. 451 et seq. or devices. If the Commissioner determines that additional time is needed to study and investigate the petition.).conditions of use must also be evaluated by the Labeling and Consumer Protection Staff of FSIS. . or poultry product subject to the Federal Meat Inspection Act (FMIA) (21 U.S.) or the Poultry Products Inspection Act (PPIA) (21 U. but not limited to. within 90 days after filing of the petition (or within 180 days if the time is extended as provided for in section 409(c)(2) of the Act). any other pertinent studies (e. Although FDA has overriding authority regarding additive safety. Additional Governmental procedures: The Commissioner will forward for publication in the FEDERAL REGISTER. a regulation prescribing the conditions under which the food additive may be safely used (including. ๒. the maximum quantity that may be used or permitted to remain in or on such food. cosmetics. as appropriate) g) Full reports of all safety studies h) Proposed tolerances (if needed) i) Environmental information (as required by the National Environmental Policy Act (NEPA) j) Ensure that consistent information is presented throughout all sections of the petition. environmental science. including those pertaining to: ๑. and egg products. the manner in which such additive may be added to or used in or on such food. as provided in the Federal Meat Inspection Act and the Poultry Products Inspection Actand related regulations. 601 et seq. and any directions or other labeling or packaging requirements for such additive deemed necessary by him to assure the safety of such use).g. ๓. discuss what type of research studies and literature reviews your company would need to conduct to successfully gain apparoval of these products in meat and poultry products. poultry. microbiology) b) After reviewing the regulatory requirements. FSIS may apply even stricter standards that take into account the unique characteristics of meat. The regulation shall describe the conditions under which the substance may be safely used in any meat product. based on the best scientific knowledge. Additives are never given permanent approval.

These should be supported by peer-reviewed references. should be followed. C. Full reports of reviews and findings should be submitted. Databases such as Science direct. what toxicological information is needed to support safety and appropriate ways of dealing with significant protocol deviations during toxicity studies should be discussed. A. construction of calibration curves and determination of limits of detection (LOD) and limits of quantification (LOQ). Each toxicity study should be uniquely identified. This may include. Literature review and research for toxicological information Determination of toxicological information regarding the food additives needs detail review of related existing data and research for potential toxicity. standards. a guidance named. this guidance refers to "National . toxicology. data for samples. Literature review and research for appropriate chemistry information Firstly. this will help confirm the proper test data be submitted. As we can see the main information must be related to: I. Food Additive Safety (OFAS) guidelines for designing toxicological studies should be consulted. Scientifically sound interpretations and conclusions should be made for the findings. chemistry.S. They are: dose-related trends. and IV. II. Environmental Protection Agency (EPA). Literature review and research for environmental submission For adequate environmental submission. Furthermore. These deviations must be discussed in the petition. Technical brochures. should be consulted. Additionally. Before initiating any studies office of Food Additive Safety (OFAS) should be consulted for protocol review before initiating any studies. III. Organization for Economic Cooperation and Development (OECD) and International conference on Harmonization (ICH) must be reviewed. material safety data sheets (MSDS) methodologies and calculations for estimating intake should be reviewed. reproducibility. environmental science. Additionally Toxicological guidance from U. B. It is better to consult FDA's Toxicology Guidance (1993 draft Red book and Redbook 2000). the analytical methodology will be adequate and the validation methodology will be adequate. related findings.Literature reviews and Research studies Literature reviews and research studies depends upon the available research findings and the required data as per the regulation of petition. The design of any study and assessment of results should be based on sound scientific principles. the magnitude and types of differences and occurrence in both sexes. Pub Med and Tox Line are recommended to follow for existing data and literature. Appropriateness of studies conducted and the effects significant deviations from FDA's guidance document should be evaluated. "Guidance for Industry: Preparing a Claim of Categorical Exclusion or an Environmental Assessment for Submission to the Center for Food Safety and Applied Nutrition". The significant deviations from appropriate guidance should be justified and possible effects on the study should be discussed. there are some factors to be considered when assessing the significance of treatmentrelated effects in toxicity studies determining the significance of differences between treated and control groups. FDA's Good Laboratory Practices (GLP) for Non-clinical studies regulations in 21 CFR part 58 must be followed for researches. any other pertinent studies. Chemistry Guidance Documents. All supporting raw data should be collected and submitted.

Code of Federal Regulations. the company should review other regulatory and technical literatures as well. other relevant researches needed to be performed to ensure the safety aspect of the proposed additives as for example. microbiological safety researches needed to be done. USDA/FSIS Federal Meat Inspection Act (FMIA) and USDA/FSIS Poultry Products Inspection Act (PPIA). Federal Meat Inspection Act. Guidance for Industry: Questions and Answers About the Petition Process. Poultry Products Inspection Act. D. Food Safety and Inspection Service. Food Drugs and Cosmetics Act. Washington. September 29. Thus. Consequently. this will provide sufficient data and information to formulate the new regulations. . our company would need to review and research in the relevant dimensions. Examples of extraordinary circumstances are discussed in the guidance. The major regulatory literatures includes. References a. D.gov/Food/GuidanceComplianceRegulatoryInformation/GuidanceDocume nts/FoodIngredientsandPackaging/ucm253328. Federal Food. In limited instances. CFR. Food Safety and Inspection Service. c. a categorical exclusion can be determined or confirmed by review of other information in the submission. 1997)".C. Code of Federal Regulations.S. 2009. to successfully gain approval of the new food additives for meat and poultry products. This will generate adequate proof for ensuring the various aspects of the additives. Food and Drug Administration. In most instances. 1906. U. Whenever testing is necessary. U.32(i) and (q). 2011. 1957. Office of the Federal Register National Archives and Records Administration.Environmental Policy Act (NEPA) implementing regulations in 21 CFR part 25 (revised in July 29. Other relevant literature reviews and researches Apart from the above mentioned researches and reviews. Government Printing Office. d. U.S.htm. FDA. Further. United States Department of Agriculture. Center for Food Safety and Applied Nutrition (CFSAN) will recommend additional information to establish that the criteria for a categorical exclusion have been met. particularly for exclusions claimed under 21 CFR 25. 1958. Available Source: http://www. Drug. If extraordinary circumstances indicate that the proposed action might have significant environmental impacts. U.S. United States Department of Agriculture. 2012. b. and Cosmetic Act.S. it is required to prepare Environmental Assessments for any normally excluded action. e. Environmental Assessment Technical Assistance Handbook should be consulted.fda.

Inorganic phosphates (e. The Food and Drug Administration (FDA) has issued a report on the toxicology of inorganic phosphates as food ingredients. An acutely high P intake adversely affects bone metabolism by decreasing bone formation and increasing bone resorption. The FDA considers phosphates as a food additive to be "generally recognized as safe. (1984) noted only a slight increase in the faecal Ca excretion rate. Spencer et al. 2010). Potential health problems High P doses in diet affects Ca and bone metabolism in a dose-dependent manner. 800 and 2000 mg/d). despite the increased S-PTH concentration. zinc phosphate. excessive use of phosphates in processed foods have increased the amount of phosphorus in human diet tremendously (EPA. high dietary P intake increased SPTH concentration in longer term situations.25(OH)2D metabolism (Calvo and Park 1996).g. In some studies. the oral intake of P in doses comparable with normal dietary intakes (495. by decreasing the number of PTH receptors. Different phosphate additives may vary in their effects on Ca absorption. a high P intake was reported to even decrease S-Ca concentration in both sexes. . 2009). In a controlled study with healthy young women. PTH and 1. 2007 and Bell et al. The key to ensuring that orthophosphate reduces lead and copper levels. 2010). as polyphosphates have decreased Ca absorption compared with ortophosphates (Kemi. When dietary P intake was increased from 800 to 2000 mg/d at varied dietary Ca intake levels (200. An acute rise in S-Pi leads to a direct increase in PTH secretion and a decrease in the renal hydroxylation of calcidiol (25(OH)D) to 1. and sodium phosphate) are added to the water to create orthophosphate. (2000) found in rats that a high-P diet reduces PTH action in the kidneys. but S-iCa may decrease due to diminished Ca absorption as a result of formation of the Ca-Pi complex in the gut. 1977 suggests that phospahte additives might have more negative effects on bone than natural P in foods (Kemi. 2010). 1245 and 1995 mg/d) with a low Ca intake (250 mg/d) increased serum parathyroid hormone (S-PTH) concentration in a dose-dependent manner (Kemi. lead and copper levels in the water will remain low." However. 2010). The different forms of phosphate salts may also vary in their responses to Ca metabolism. a) increase in serum parathyroid hormone (S-PTH) High P in diet has found to increase S-PTH level. As a result. The coating serves as a liner that keeps corrosion elements in water from dissolving some of the metal in the drinking water. while U-Ca excretion decreased significantly. 2010). (20 pts) What are the potential health problems with a high intake of phosphorus in drinking water? Phosphorus in drinking water Public water systems (PWSs) commonly add phosphates to the drinking water as a corrosion inhibitor to prevent the leaching of lead and copper from pipes and fixtures. 745.25(OH)2D reduces Ca absorption and results in hypocalcaemia and elevated PTH secretion. is for PWSs to maintain proper orthophosphate levels ((EPA. In some studies with humans. Two studies done by Karp et al. but no studies have properly investigated the dose-response effects of dietary P intakes(Kemi. In rats fed a high-P diet. Strong evidence has emerged in animals that high-P diets increase PTH secretion. b) effect in Calcium metabolism The high P intake in diet causes a decrease in serum ionized Ca (S-iCa) concentration. phosphoric acid. The mechanism underlying the impact of high P intake on S-iCa remains unclear. 2009). The health effects of drinking water with phosphates are not known. Masuyama et al. Below are the complications related with high amount of phosphorus in various diet. A decreasing S-1. c) effect in Bone metabolism According to several animal and limited human intervention studies.25(OH) 2D in the kidney. which forms a protective coating of insoluble mineral scale on the inside of service lines and household plumbing. the development of nephrocalcinosis and diminished kidney function was more severe with P ingested in the form of polyphosphates than in the form of ortophosphates ( Kemi..3. a high P intake affects bone metabolism through alterations in Ca.

2008). . Among patients with end-stage renal disease and diabetes. 2010).96(03):545-552. excess P intake has very damaging effects on bone. References: a) Calvo. In healthy humans. Fukagawa . 47:989-994. impaired 1. Park . Recent results suggest that an excessive P intake may be involved in this vascular calcification process.com/link/portal/23002/23015/Article/24942/Why-do-watersystems-add-phosphate-to-drinking-water-What-are-the-health-effects-of-drinking-water-containing phosphates. An alarming rise has been seen among Western populations in the incidence of type 2 diabetes. 2006. Kärkkäinen and C. 2006). Changing phosphorus content of the U. as "chronic kidney disease" might lead to a "multifactorial bone disorder". M. Why do water systems add phosphate to drinking water? What are the health effects of drinking water containing phosphates. British Journal of Nutrition. September 29. Inter Med. 2012. Tanaka ane M. In early renal failure. a major cause of endstage renal disease. M. decreased S-1. 2010). d) Kemi.. To prevent hyperphosphataemia.When renal function is impaired. E. while the intermittent administration of PTH has the opposite effects. Thesis. High phosphorus intakes acutely and negatively affect Ca and bone metabolism in a dosedependent manner in healthy young females. vascular calcification correlates highly with cardiovascular disease mortality.S.United States Environmental Protection Agency. 2010. d) Vascular Calcification High S-Pi is thought to be an indirect cause of vascular calcification.mechanism: Mainly.S. even in healthy humans (Kemi et al. However. J Nutr . a continuously high SPTH results in higher bone resorption and release of Ca and P from bone.25(OH)2D production and low S-iCa levels resulting from impaired Ca absorption stimulate PTH secretion and promote parathyroid gland hyperplasia (overgrowth of the parathyroid gland due to an increased number of cells) (Komaba et al. M. CKD-MBD . 2008.. in which dietary P restrict ion is a part of the treatment. patients with renal disease use P binders to reduce dietary P absorption and limit their consumption of foods with high P content (Kemi. Effects of dietary phosphorus and calcium-to phosphorus ratio on calcium and bone metabolism in healthy 20. E. 2009. the effects of P on bone metabolism are mediated through the increased PTH secretion. V. leading to hyperphosphataemia.to 43-year-old Finnish women. when renal disease progresses. Increase in high intake of P aggravates this condition (Kemi.126:1168S-1180S. Treatment of secondary hyperparathyroidism is essential in the management of CKD-MBD. b) EPA. e) Complicaions in case of Renal Failure When kidney function is reduced. c) Kemi. U. 1996. Secondary hyperparathyroidism (accelerated function of the parathyroid gland) is a common finding in these circumstances. Treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Urinary phosphate (U-Pi) excretion decreases and more P remains inside the body.K. M. V. J. University of Helsinki. e) Komaba H. Department of Food and Environmental Sciences.supportportal.. and Y. LambergAllardt.25(OH)2D and S-iCa contribute to increased secretion of PTH. diet: potential for adverse effects on bone. Available Source: http://safewater.