- Email: [email protected]
Determining safety criteria
FOOD IRRADIATION REVISITED
Determining Safety Criteria Clyde A. Takeguchi, PhD From Phoenix Regulatory Associates, Ltd., Sterling, Virginia, USA I have been asked to provide comment on food irradiation because of a series of letters in response to an editorial by Tritsch.1 Instead of a direct response to specific comments, I have focused on the issue of determining criteria for establishing safety of food irradiation and whether these criteria have been satisfied with available studies. I know that this will not be the end of the discussion, but I hope that any discussion on a controversial issue is based on the complete body of information. I was introduced to food irradiation as a quarantine treatment for fruits and vegetables grown in Hawaii. As a graduate student in the Food Science Department at the University of Hawaii during the mid-1960s, I was aware of the early work of Ernest Akamine and others on the use of food irradiation to treat papaya and other tropical fruits as a quarantine treatment to control the medfly and assist in the export of Hawaii’s agricultural crops. About a decade later, I accepted a job at the Food and Drug Administration’s (FDA) Division of Food and Color Additives in the Bureau of Foods (now the Center for Food Safety and Applied Nutrition). One of the projects I inherited was an “oddball” additive called food irradiation. In 1958, Congress amended the Federal Food, Drug, and Cosmetic Act by passing the Food Additives Amendment of 1958 (the 1958 Amendment).2 The term sources of radiation intended for use in processing or treating food is included in the definition of the term food additive. The 1958 Amendment shifted the burden of establishing safety from the FDA to industry and allowed industry to add a new additive to food based on adequate information that the new additive was safe under the proposed conditions of use and that the procedure for establishing safety was similar to the premarket review process for new drugs, although it was not based on an assessment of risk and benefit. In defining the safety of a food additive, Congress determined that safety was “reasonable certainty that no harm will result from the proposed use of an additive. It does not—and cannot—require proof beyond any possible doubt that no harm will result under any conceivable circumstance.”3 The definition of safety codified in 21 CFR 170.3(i) is based on the legislative history of the 1958 Amendment, which emphasized that it is impossible to establish absolute safety and included the following factors for consideration: 1. The probable consumption of the substance and of any substance formed in or on food because of its use. 2. The cumulative effect of the substance in the diet, taking into account any chemically or pharmacologically related substance or substances in such diet. 3. Safety factors that, in the opinion of experts qualified by scientific training and experience to evaluate the safety of food and food ingredients, are generally recognized as appropriate.4 Because of renewed interest in food irradiation in the 1970s, the FDA established in 1979 an internal committee, the Bureau of Foods Irradiated Foods Committee (BFIFC), to reassess the issue of food irradiation.5 BFIFC used knowledge available on radiation
Correspondence to: Clyde A. Takeguchi, PhD, Executive Vice President, Phoenix Regulatory Associates, Ltd., 21525 Ridgetop Circle, Suite 240, Sterling, VA 20166, USA. E-mail: [email protected] Nutrition 18:759 –760, 2002 ©Elsevier Science Inc., 2002. Printed in the United States. All rights reserved.
chemistry to estimate the amounts, types, and potential toxicity of compounds formed at irradiation and recommended that foods irradiated at doses of less than 1 kGy, or foods representing a very small fraction of the diet, should be exempt from the requirements for toxicologic testing. For food treated by higher processing doses, BFIFC recommended a battery of short-term mutagenicity tests and 90-d feeding studies in two species (one rodent and one non-rodent), where the tested article contains the maximum concentration of radiolytic products. A task group established after issuance of the BFIFC report reviewed the available animal feeding and mutagenicity studies and found that those studies did not appear to show any toxicologic effects of irradiated food and concurred with the BFIFC recommendations. Safety of the process under the conditions of use varies for food irradiation according to the specific use. For live organisms, the more complex the organism, the more sensitive it is to irradiation. For example, insects are more sensitive than microorganisms, and vegetative cells more sensitive than spores. To control insects in food, the process should allow a low dose (usually a dose range to allow for processing conditions) that will kill or sterilize the egg or larvae without being phytotoxic to the fruit or vegetable. For a process to control microorganisms in food, the “pasteurization” dose is sufficient to decrease the amount of pathogenic microorganisms but not to eliminate the spoilage microorganisms so the consumer can detect food spoilage. The process for shelf-stable irradiated meat products for limited use by the astronauts consists of a preirradiation process that includes heating to inactivate the enzymes in meat, vacuum packaging to eliminate oxygen, and freezing to minimize free-radical reaction. The safety evaluation for an irradiated food includes an evaluation on the type and number of possible products formed during the process. The amount and type of products formed are influenced by the concentration of possible reactants (including water), relative rate constants of competing reactions, the mobility of the free radicals, temperature, and the presence (or absence) of oxygen. The safety evaluation needs to acknowledge that the food consists of individual cells that are highly structured and that reactions in a cell as a result of irradiation are not comparable to a reaction of cellular components in a simple solution. For example, Tritsch cited studies on the formation of toxic compounds produced by the reaction of peroxy radicals with sugar molecules during the irradiation of simple sugar solutions.1,6 The safety decision acknowledged the formation of such toxic compounds and the fact that sugars and other food components are normally compartmentalized. Thus, the irradiation of foods such as mango pulp or strawberries do not produce peroxy radicals because of the presence of other reactive molecules such as organic acids, phenols, and lipids.7 It is interesting to note that two articles appeared in the same issue as the Tritsch article discussing the consequences of the local action of free radicals in human tissue.8,9 One important requirement for any food process is the establishment of a scheduled process that provides for the use of a written procedure that maximizes the advantages of the process, minimizes the unwanted effects, and provides adequate directions to produce a safe product consistently under current good manufacturing (and good irradiation) conditions. The FDA recommends that safety feeding studies use food treated identical or similar to commercial conditions to evaluate the safety of the process. The 0899-9007/02/$22.00 PII S0899-9007(02)00866-3
760
Takeguchi
shelf-stable process is a hazard analysis and critical control point (HACCP) plan that requires a processing dose that is 12 times the lethal dose for Clostridium botulinum, which is similar to the requirement for canning, which is 12 times the thermal death time for C. botulinum to ensure a safe, canned product. Except for the studies done by the Department of Defense for shelf-stable products, the studies done in the 1950s through the 1970s used food irradiated according to experimental protocol that was not intended for commercial use. Many studies exaggerated the dose to provide a greater safety factor, but resulted in food that was sterile but inedible. These studies have provided answers to some of the safety questions but are not without controversy. For example, different sources were used to irradiate the food, and many of the toxicology studies were contracts by the US Army to universities and laboratories. The results were included in quarterly and final reports, but some were not published as journal articles. Despite these limitations, the toxicology studies on foods treated under a variety of conditions, taken in total, have provided evidence that food irradiation is a safe process for treating food. One of the studies cited by Tritsch1 is a case in point. Tritsch referred to a study by Monsen10,11 in which heart lesions were observed in mice of the Cb and Strong A strains fed a mixture of irradiated foods (pork loin, evaporated milk, blanched carrots, chicken, and white potatoes). Monsen reported that 17.5% of the Cb mice and 2% of the Strong A mice on the irradiated diet died or were killed because of rupture or dilatation of the left auricle of the heart and stated that the higher incidence of the Cb strain suggested a genetic predisposition. Based on preliminary studies, Monsen10 –12 suggested that the evaporated milk was the responsible ingredient, and further study suggested that the results were related to iron and copper deficiencies. The study was repeated at the US Army Medical Research and Nutrition Laboratory in Denver by Thompson et al.13; they used the same strains of mice and the same irradiated food mixture, but they could not duplicate the effect. Thompson et al.13stated that similar lesions reported by Monsen10 were reported by others to occur in old inactive breeders of the BALB/C strain of mice (Cb strain is BALB/C with the milk factor). The issue of polyploidy discussed by Tritsch1 with regard to malnourished Indian children fed irradiated wheat has been discussed and argued ever since completion of the study in 1975. Polyploidy and other toxicology issues dealing with animal feeding studies were discussed and resulted in the FDA’s conclusion that none of the objections provided new issues or information that would change its decision on safety and did not justify a hearing.14,1514,15 The FDA’s decision was based on a fair evaluation of the complete record and included published articles, unpublished
Nutrition Volume 18, Number 9, 2002 reports, and correspondence.14 This evaluation was part of the FDA’s rule-making procedure on food irradiation that spanned close to 10 y and allowed for public comment. The FDA discussed various issues, including the production and safety of radiolytic products such as irradiated sugar solutions, free radicals, hydrogen peroxide, formaldehyde, and benzene. Other uses of food irradiation will continue to be evaluated by the FDA and other authoritative bodies internationally. Food irradiation will not replace other food processes, but there may be specific food products for which it may be the process of choice. There will always be controversy and diversity of opinions on such topics as food irradiation. For meaningful dialogue, all participants need to base their arguments on the complete record, not on a selected portion. Once a decision on safety is made, the marketplace should determine the acceptance or rejection of an alternative process, not the use of economic terrorism or blackmail.
REFERENCES 1. Tritsch GL. Food irradiation. Nutrition 2000;16:698 2. Food and Drug Administration. Federal food, drug, and cosmetic act, in compilation of laws enforced by the U.S. Food and Drug Administration and related statutes, Vol 1. Washington, DC: Food and Drug Administration, 1996:5 3. Food Additives Amendment of Senate Report No. 2422, 85th Congress, 2d Session, 1958 4. Food and Drug Administration, 170.3 Definitions, Code of Federal Regulations, Title 21, Parts 170 to 199, 2001, p. 5 5. Pauli GH, Tarantino LM. FDA regulatory aspects of food irradiation. J Food Protect 1995;58:209 6. Steward FC, Holsten RD, Sugii M. Direct and indirect effects of radiation: the radiolysis of sugar. Nature 1967;213:178 7. Niemand JG, den Drijver L, Pretorius CJ, Holzapfel CW, van der Linde HJ. A study of the mutagenicity of irradiated sugar solutions: implications for the radiation preservation of subtropical fruits. J Agric Food Chem 1983;31:1016 8. Freeman BA. Oxygen. The air-borne nutrient that both sustains and threatens life. Nutrition 2000;16:478 9. Thomas MJ. The role of free radicals and antioxidants. Nutrition 2000;16:716 10. Monsen H. Heart lesions in mice induced by feeding irradiated foods. Fed Proc 1960;19:1031 11. Monsen H. Heart lesions in mice. Final report. Unpublished document; United States Army Contract no. DA-49-007-MD-794. 1963 12. Monsen H. Heart lesions in mice. Addendum. Unpublished document; United States Army Contract no. DA-49-007-MD-794. 1965 13. Thompson SW, Hunt RD, Ferrell J, Jenkins ED, Monsen H. Histopathology of mice fed irradiated foods. J Nutr 1965;87:274 14. Food and Drug Administration. Irradiation in the production, processing, and handling of food. Final rule. Fed Reg 1986;51:13376 15. Food and Drug Administration. Irradiation in the production, processing, and handling of food. Final rule, denial of requests for hearing and response to objections. Fed Reg 1988;53:53176
Determining Safety Criteria Clyde A. Takeguchi, PhD From Phoenix Regulatory Associates, Ltd., Sterling, Virginia, USA I have been asked to provide comment on food irradiation because of a series of letters in response to an editorial by Tritsch.1 Instead of a direct response to specific comments, I have focused on the issue of determining criteria for establishing safety of food irradiation and whether these criteria have been satisfied with available studies. I know that this will not be the end of the discussion, but I hope that any discussion on a controversial issue is based on the complete body of information. I was introduced to food irradiation as a quarantine treatment for fruits and vegetables grown in Hawaii. As a graduate student in the Food Science Department at the University of Hawaii during the mid-1960s, I was aware of the early work of Ernest Akamine and others on the use of food irradiation to treat papaya and other tropical fruits as a quarantine treatment to control the medfly and assist in the export of Hawaii’s agricultural crops. About a decade later, I accepted a job at the Food and Drug Administration’s (FDA) Division of Food and Color Additives in the Bureau of Foods (now the Center for Food Safety and Applied Nutrition). One of the projects I inherited was an “oddball” additive called food irradiation. In 1958, Congress amended the Federal Food, Drug, and Cosmetic Act by passing the Food Additives Amendment of 1958 (the 1958 Amendment).2 The term sources of radiation intended for use in processing or treating food is included in the definition of the term food additive. The 1958 Amendment shifted the burden of establishing safety from the FDA to industry and allowed industry to add a new additive to food based on adequate information that the new additive was safe under the proposed conditions of use and that the procedure for establishing safety was similar to the premarket review process for new drugs, although it was not based on an assessment of risk and benefit. In defining the safety of a food additive, Congress determined that safety was “reasonable certainty that no harm will result from the proposed use of an additive. It does not—and cannot—require proof beyond any possible doubt that no harm will result under any conceivable circumstance.”3 The definition of safety codified in 21 CFR 170.3(i) is based on the legislative history of the 1958 Amendment, which emphasized that it is impossible to establish absolute safety and included the following factors for consideration: 1. The probable consumption of the substance and of any substance formed in or on food because of its use. 2. The cumulative effect of the substance in the diet, taking into account any chemically or pharmacologically related substance or substances in such diet. 3. Safety factors that, in the opinion of experts qualified by scientific training and experience to evaluate the safety of food and food ingredients, are generally recognized as appropriate.4 Because of renewed interest in food irradiation in the 1970s, the FDA established in 1979 an internal committee, the Bureau of Foods Irradiated Foods Committee (BFIFC), to reassess the issue of food irradiation.5 BFIFC used knowledge available on radiation
Correspondence to: Clyde A. Takeguchi, PhD, Executive Vice President, Phoenix Regulatory Associates, Ltd., 21525 Ridgetop Circle, Suite 240, Sterling, VA 20166, USA. E-mail: [email protected] Nutrition 18:759 –760, 2002 ©Elsevier Science Inc., 2002. Printed in the United States. All rights reserved.
chemistry to estimate the amounts, types, and potential toxicity of compounds formed at irradiation and recommended that foods irradiated at doses of less than 1 kGy, or foods representing a very small fraction of the diet, should be exempt from the requirements for toxicologic testing. For food treated by higher processing doses, BFIFC recommended a battery of short-term mutagenicity tests and 90-d feeding studies in two species (one rodent and one non-rodent), where the tested article contains the maximum concentration of radiolytic products. A task group established after issuance of the BFIFC report reviewed the available animal feeding and mutagenicity studies and found that those studies did not appear to show any toxicologic effects of irradiated food and concurred with the BFIFC recommendations. Safety of the process under the conditions of use varies for food irradiation according to the specific use. For live organisms, the more complex the organism, the more sensitive it is to irradiation. For example, insects are more sensitive than microorganisms, and vegetative cells more sensitive than spores. To control insects in food, the process should allow a low dose (usually a dose range to allow for processing conditions) that will kill or sterilize the egg or larvae without being phytotoxic to the fruit or vegetable. For a process to control microorganisms in food, the “pasteurization” dose is sufficient to decrease the amount of pathogenic microorganisms but not to eliminate the spoilage microorganisms so the consumer can detect food spoilage. The process for shelf-stable irradiated meat products for limited use by the astronauts consists of a preirradiation process that includes heating to inactivate the enzymes in meat, vacuum packaging to eliminate oxygen, and freezing to minimize free-radical reaction. The safety evaluation for an irradiated food includes an evaluation on the type and number of possible products formed during the process. The amount and type of products formed are influenced by the concentration of possible reactants (including water), relative rate constants of competing reactions, the mobility of the free radicals, temperature, and the presence (or absence) of oxygen. The safety evaluation needs to acknowledge that the food consists of individual cells that are highly structured and that reactions in a cell as a result of irradiation are not comparable to a reaction of cellular components in a simple solution. For example, Tritsch cited studies on the formation of toxic compounds produced by the reaction of peroxy radicals with sugar molecules during the irradiation of simple sugar solutions.1,6 The safety decision acknowledged the formation of such toxic compounds and the fact that sugars and other food components are normally compartmentalized. Thus, the irradiation of foods such as mango pulp or strawberries do not produce peroxy radicals because of the presence of other reactive molecules such as organic acids, phenols, and lipids.7 It is interesting to note that two articles appeared in the same issue as the Tritsch article discussing the consequences of the local action of free radicals in human tissue.8,9 One important requirement for any food process is the establishment of a scheduled process that provides for the use of a written procedure that maximizes the advantages of the process, minimizes the unwanted effects, and provides adequate directions to produce a safe product consistently under current good manufacturing (and good irradiation) conditions. The FDA recommends that safety feeding studies use food treated identical or similar to commercial conditions to evaluate the safety of the process. The 0899-9007/02/$22.00 PII S0899-9007(02)00866-3
760
Takeguchi
shelf-stable process is a hazard analysis and critical control point (HACCP) plan that requires a processing dose that is 12 times the lethal dose for Clostridium botulinum, which is similar to the requirement for canning, which is 12 times the thermal death time for C. botulinum to ensure a safe, canned product. Except for the studies done by the Department of Defense for shelf-stable products, the studies done in the 1950s through the 1970s used food irradiated according to experimental protocol that was not intended for commercial use. Many studies exaggerated the dose to provide a greater safety factor, but resulted in food that was sterile but inedible. These studies have provided answers to some of the safety questions but are not without controversy. For example, different sources were used to irradiate the food, and many of the toxicology studies were contracts by the US Army to universities and laboratories. The results were included in quarterly and final reports, but some were not published as journal articles. Despite these limitations, the toxicology studies on foods treated under a variety of conditions, taken in total, have provided evidence that food irradiation is a safe process for treating food. One of the studies cited by Tritsch1 is a case in point. Tritsch referred to a study by Monsen10,11 in which heart lesions were observed in mice of the Cb and Strong A strains fed a mixture of irradiated foods (pork loin, evaporated milk, blanched carrots, chicken, and white potatoes). Monsen reported that 17.5% of the Cb mice and 2% of the Strong A mice on the irradiated diet died or were killed because of rupture or dilatation of the left auricle of the heart and stated that the higher incidence of the Cb strain suggested a genetic predisposition. Based on preliminary studies, Monsen10 –12 suggested that the evaporated milk was the responsible ingredient, and further study suggested that the results were related to iron and copper deficiencies. The study was repeated at the US Army Medical Research and Nutrition Laboratory in Denver by Thompson et al.13; they used the same strains of mice and the same irradiated food mixture, but they could not duplicate the effect. Thompson et al.13stated that similar lesions reported by Monsen10 were reported by others to occur in old inactive breeders of the BALB/C strain of mice (Cb strain is BALB/C with the milk factor). The issue of polyploidy discussed by Tritsch1 with regard to malnourished Indian children fed irradiated wheat has been discussed and argued ever since completion of the study in 1975. Polyploidy and other toxicology issues dealing with animal feeding studies were discussed and resulted in the FDA’s conclusion that none of the objections provided new issues or information that would change its decision on safety and did not justify a hearing.14,1514,15 The FDA’s decision was based on a fair evaluation of the complete record and included published articles, unpublished
Nutrition Volume 18, Number 9, 2002 reports, and correspondence.14 This evaluation was part of the FDA’s rule-making procedure on food irradiation that spanned close to 10 y and allowed for public comment. The FDA discussed various issues, including the production and safety of radiolytic products such as irradiated sugar solutions, free radicals, hydrogen peroxide, formaldehyde, and benzene. Other uses of food irradiation will continue to be evaluated by the FDA and other authoritative bodies internationally. Food irradiation will not replace other food processes, but there may be specific food products for which it may be the process of choice. There will always be controversy and diversity of opinions on such topics as food irradiation. For meaningful dialogue, all participants need to base their arguments on the complete record, not on a selected portion. Once a decision on safety is made, the marketplace should determine the acceptance or rejection of an alternative process, not the use of economic terrorism or blackmail.
REFERENCES 1. Tritsch GL. Food irradiation. Nutrition 2000;16:698 2. Food and Drug Administration. Federal food, drug, and cosmetic act, in compilation of laws enforced by the U.S. Food and Drug Administration and related statutes, Vol 1. Washington, DC: Food and Drug Administration, 1996:5 3. Food Additives Amendment of Senate Report No. 2422, 85th Congress, 2d Session, 1958 4. Food and Drug Administration, 170.3 Definitions, Code of Federal Regulations, Title 21, Parts 170 to 199, 2001, p. 5 5. Pauli GH, Tarantino LM. FDA regulatory aspects of food irradiation. J Food Protect 1995;58:209 6. Steward FC, Holsten RD, Sugii M. Direct and indirect effects of radiation: the radiolysis of sugar. Nature 1967;213:178 7. Niemand JG, den Drijver L, Pretorius CJ, Holzapfel CW, van der Linde HJ. A study of the mutagenicity of irradiated sugar solutions: implications for the radiation preservation of subtropical fruits. J Agric Food Chem 1983;31:1016 8. Freeman BA. Oxygen. The air-borne nutrient that both sustains and threatens life. Nutrition 2000;16:478 9. Thomas MJ. The role of free radicals and antioxidants. Nutrition 2000;16:716 10. Monsen H. Heart lesions in mice induced by feeding irradiated foods. Fed Proc 1960;19:1031 11. Monsen H. Heart lesions in mice. Final report. Unpublished document; United States Army Contract no. DA-49-007-MD-794. 1963 12. Monsen H. Heart lesions in mice. Addendum. Unpublished document; United States Army Contract no. DA-49-007-MD-794. 1965 13. Thompson SW, Hunt RD, Ferrell J, Jenkins ED, Monsen H. Histopathology of mice fed irradiated foods. J Nutr 1965;87:274 14. Food and Drug Administration. Irradiation in the production, processing, and handling of food. Final rule. Fed Reg 1986;51:13376 15. Food and Drug Administration. Irradiation in the production, processing, and handling of food. Final rule, denial of requests for hearing and response to objections. Fed Reg 1988;53:53176