Threshold of toxicological concern for chemical substances present in the diet: A practical tool for assessing the need for toxicity testing

Food and Chemical Toxicology

Volumn 38, Issue 2-3, 2000, Pages 255-312

  Kroes, R ^a   Galli, C ^b   Munro, I ^c   Schilter, B ^d   Tran, L A ^e   Walker, R ^f   Wurtzen G ^g  

^a UTRECHT UNIVERSITY   (Netherlands)

^b UNIVERSITY OF MILAN   (Italy)

^c CanTox Inc   (Canada)

^d NESTLÉ RESEARCH CENTER   (Switzerland)

^e International Life Sciences Institute of Europe   (Belgium)

^f UNIVERSITY OF SURREY   (United Kingdom)

^g Coca Cola Nordic and N Eurasia Div ^*  (Denmark)

Author keywords

NOEL; Structural alerts; Threshold; Toxicological endpoints

Indexed keywords

CHEMICAL COMPOUND; FOOD ADDITIVE;

ALLERGENICITY; CARCINOGENICITY; DATA BASE; DIET; ENDOCRINE DISEASE; EXPOSURE; FOOD AND DRUG ADMINISTRATION; FOOD SAFETY; HEALTH HAZARD; IMMUNOTOXICITY; MAXIMUM ALLOWABLE CONCENTRATION; NEUROTOXICITY; REVIEW; TERATOGENICITY; TOXICITY TESTING;

ANIMALS; CARCINOGENICITY TESTS; DIET; DOSE-RESPONSE RELATIONSHIP, DRUG; ENDOCRINE SYSTEM; FOOD CONTAMINATION; FOOD HYPERSENSITIVITY; HUMANS; MUTAGENICITY TESTS; NO-OBSERVED-ADVERSE-EFFECT LEVEL; REFERENCE VALUES; THRESHOLD LIMIT VALUES; TOXICITY TESTS; UNITED STATES; UNITED STATES FOOD AND DRUG ADMINISTRATION; XENOBIOTICS;

ANIMALIA; APOGON BRACHYGRAMMUS;

EID: 0034010667     PISSN: 02786915     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0278-6915(99)00120-9     Document Type: Review

References (111)

1. Anthony D. C. and Graham D. G. (1990) Cassarett and Doull's Toxicology, ed. C. D. Klaassen, M. O. Amdur and J. Doull, pp. 407-431. Macmillan, New York.
2. Ashby J., Tennant R. W. Chemical structure, Salmonella mutagenicity and extent of carcinogenicity as indicators of genotoxic carcinogenesis among 222 chemicals tested in rodents by the US NCI/NTP. Mutation Research. 204:1988;17-115.
3. Barkhem T., Carlson B., Nilsson Y., Enmark E., Gustafsson J.-A., Nilsson S. Differential response of estrogen receptor a and estrogen receptor b to partial estrogen agonists/antagonists. Molecular Pharmacology. 54:1998;105-112.
4. Barnard R. C. Scientific method and risk assessment. Regulatory Toxicology and Pharmacology. 19:1994;211-218.
5. Beck B. D., Calabrese E. J. and Anderson P. D. (1989) The use of toxicology in the regulatory process. In Principles and Methods of Toxicology, ed. A. W. Hayes, 2nd edn, pp. 1-28. Raven Press, New York.
6. Beck B. D., Conolly R. B., Dourson M. L., Guth D., Hattis D., Kimmel C., Lewis C. Symposium overview. Improvements in quantitative non-cancer risk assessment. Fundamental and Applied Toxicology. 20:1993;1-14.
7. Biegel L. B., Cook J. C., O'Connor J. C., Aschiero M., Arduengo A. J., Slone T. W. Subchronic toxicity study in rats with 1-methyl-3-propylimidazole-2-thione (PTI): effects on the thyroid. Fundamental and Applied Toxicology. 27:1995;185-194.
8. Bousquet J. (1994) Le diagnostic de l'allergie alimentaire. In Allergie Alimentaire. Dossier scientifique de l'Institut Français pour la Nutrition. No. 4.
9. Bousquet J., Björkstén B., Bruijnzeel-Koomen C. A. F. M., Huggett A., Ortolani C., Warner J. O., Smith M. Scientific criteria and the selection of allergenic foods for product labelling. Allergy. 53:1999;1-19.
10. Buster J. E., Meis P. J., Hobel C. J., Marshall J. R. Journal of Clinical Endocrinology and Metabolism. 46:1978;907.
11. Calabrese E. J., Baldwin L. A., Kostecki P. T., Potter T. L. A toxicologically based weight-of-evidence methodology for the relative ranking of chemicals of endocrine disruption potential. Regulatory Toxicology and Pharmacology. 26:1997;36-40.
12. Chapin R. E., Stevens J. T., Hughes C. L., Kelce W. R., Hess R. A., Daston G. P. Endocrine modulation of reproduction. Symposium overview. Fundamental and Applied Toxicology. 29:1996;1-17.
13. Chernoff N., Kavlock R. J. An in vivo teratology screen utilizing pregnant mice. Journal of Toxicology and Environmental Health. 10:1982;541-550.
14. Colborn T. Environmental estrogens: health implications for humans and wildlife. Environmental Health Perspectives. 103:(Suppl. 7):1995;135-136.
15. Cramer G. M., Ford R. A., Hall R. L. Estimation of toxic hazard: A decision tree approach. Food and Cosmetics Toxicology. 16:1978;255-276.
16. CSTEE (1999) CSTEE Opinion on Human and Wildlife Health Effects of Endocrine Disrupting Chemicals, with Emphasis on Wildlife and on Ecotoxicology Test Methods. Report of the Working Group on Endocrine Disrupters of the Scientific Committee on Toxicity, Ecotoxicity and the Environment (CSTEE) of EC-DG XXIV.
17. Dean J. H. and Murray M. J. (1990) Toxic responses of the immune system. In Cassarett and Doull's Toxicology, ed. C. D. Klaassen, M. O. Amdur and J. Doull, pp. 282-335. Macmillan, New York.
18. Desi I. Neurotoxicological investigation of pesticides in animal experiments. Neurobehavioral Toxicology and Teratology. 5:1983;503-515.
19. Dewdney J. M., Maes L., Raynaud J. P., Blanc F., Scheid J. P., Jackson T., Lens S., Verschueren C. Risk assessment of antibiotic residues of β-lactams and macrolides in food products with regard to their immuno-allergic potential. Food and Chemical Toxicology. 29:1991;477-483.
20. DFG (1998) Hormonell aktive Stoffe in Lebensmitteln. Report of the Deutsche Forschungsgemeinschaft.
21. Dorgan J. F., et al. Serum sex hormone levels are related to breast cancer risk in postmenopausal women. Environmental Health Perspectives. 105:(Suppl. 3):1997;583-585.
22. Dourson M. L., Felter S. P., Robinson D. Evaluation of science-based uncertainty factors in noncancer risk assessment. Regulatory Toxicology and Pharmacology. 24:1996;108-120.
23. Dutch Health Council (1991) Immunotoxiciteit van stoffen.
24. EC (1996) European Workshop on the Impact of Endocrine Disrupters on Human Health and Wildlife. 2-4 December 1996, Weybridge (UK). Report of Proceedings. Published by the EC-DG XII Environment and Climate Research Programme.
25. Guidelines for the health assessment of suspect developmental toxicants. Federal Register. 51:1986;34027-34040.
26. EPA (1997) Special report on environmental endocrine disruption: An effects assessment and analysis. Risk assessment forum. US Environmental Protection Agency. February 1997. EPA/630/R-96/012.
27. EPA (1998) Final Report of the US EPA. Endocrine Disruptor Screening Testing Advisory Committee (EDSTAC).
28. Eubanks M. W. Hormones and health. Environmental Health Perspectives. 105:1997;482-487.
29. FAO (1995) Report of the FAO Technical Consultation on Food Allergies. Rome, Italy, 13-14 November 1995, Food and Agriculture Organisation of the United Nations.
30. FDA (1982) Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives used in Food. Redbook. US Food and Drug Administration, Bureau of Foods, Washington, DC.
31. Feldman D. Ketoconazole and other imidazole derivatives as inhibitors of steroidogenesis. Endocrine Reviews. 7:1986;409-420.
32. Frawley J. P. Scientific evidence and common sense as a basis for food-packaging regulations. Food and Cosmetics Toxicology. 5:1967;293-308.
33. Fullerton F. R., Kushmaul R. J., Suber R. L., Littlefield N. A. Influence of oral administration of sulphamethazine on thyroid hormone levels in Fisher 344 rats. Journal of Toxicology and Environmental Health. 22:1987;175-185.
34. Goebel R., Kuss E. Journal of Clinical Endocrinology and Metabolism. 39:1974;969.
35. Gold L. S., Sawyer C. B., Magaw R., Backman G. M., Veciana M., Levinson R., Hooper N. K., et al. A carcinogenic potency database of the standardized results of animal bioassays. Environmental Health Perspectives. 58:1984;9-319.
36. Gold L. S., Slone T. H., Bernstein L. Summary of carcinogenic potency and positivity for 492 rodent carcinogens in the carcinogenic potency database. Environmental Health Perspectives. 79:1989;259-272.
37. Goldey E. S., Tilson H. A., Crofton K. M. Implications of the use of neonatal birth weight, growth, viability, and survival data for predicting developmental neurotoxicity: a survey of the literature. Neurotoxicology and Teratology. 17:1995;313-332.
38. Hammond B., Katzenellenbogen B. S., Kranthammer N., McConnell J. Estrogenic activity of the insecticide chlordecone (kepone) and interaction with uterine estrogen receptors. Proceedings of the National Academy of Sciences of the U.S.A. 76:1979;6641-6645.
39. Hannuksela M., Haahtela T. Hypersensitivity reactions to food additives. Allergy. 42:1987;561-575.
40. Hayes J. R. and Campbell T. C. (1986) Food additives and contaminants. In Cassarett and Doull's Toxicology, ed. C. D. Klaassen, M. O. Amdur and J. Doull, 3rd edn, pp. 774-776. Macmillan, New York.
41. Hourihane J.O'B., Kilburn S. A., Nordlee J. A., Hefle S. L., Taylor S. L., Warner J. O. An evaluation of the sensitivity of subjects with peanut allergy to very low doses of peanut protein: a randomized, double-blind, placebo-controlled food challenge study. Journal of Allergy and Clinical Immunology. 100:1997;596-600.
42. IPCS (1994) Assessing human health risks of chemicals: derivation of guidance values for health-based exposure limits. WHO Environmental Health Criteria No. 170. International Programme on Chemical Safety.
43. Janssen I., Reichart I., Bunke D., Waechter F. and Rufli H. (1997) Phytoestrogens and hormonally active environmental chemicals. Possibilities and limitations of comparative risk evaluations. Oko-Institute for Applied Ecology e.V.
44. Kägi M. K., Wüthrich B., Johansson S. G. O. Campari-orange anaphylaxis due to carmine allergy. Lancet. 344:1994;60-61.
45. Katagiri H., Distler W., Freeman R. K. and Goebelmann U. (1976) American Journal of Obstetrics and Gynecology. 124, 272.
46. Kavlock, et al. Research needs for the risk assessment of health and environmental effects of endocrine disrupters: a report of the US EPA-sponsored workshop. Environmental Health Perspectives. 104:(Suppl. 4):1996;715-740.
47. Krewski D., Szyskowicz M., Rosenkranz H. Quantitative factors in chemical carcinogenesis: variation in carcinogenic potency. Regulatory Toxicology and Pharmacology. 12:1990;13-29.
48. Kuhnau J. The flavonoids. A class of semi-essential food components: their role in human nutrition. World Review of Nutrition and Dietetics. 24:1976;117-191.
49. Kuiper G. G. J. M., Lemmen J. G., Carlsson B., Corton J. C., Safe S. H., Van der Saag P. T., Van der Burg B., Gustafsson J-A. Interaction of estrogenic chemicals and phytoestrogens with estrogen receptor b. Endocrinology. 139:1997;4252-4263.
50. Landgren B. M., Undén A. L., Diczfalusy E. Acta Endocrinologica. 94:1980;89.
51. th Meeting of the Joint FAO/WHO Expert Committee on Food Additives. WHO Food Additives Series. No. 39.
52. Lenton E. A., Cooke I. D., Sampson G. A., Sexton L. Clinical Endocrinology. 9:1978;37.
53. Lessof M. H. (1994) Food allergy and other adverse reactions to food. ILSI Europe Concise Monograph Series. ILSI Press.
54. Lewis S. C., Lynch J. R., Nikiforov A. I. A new approach to deriving community exposure guidelines from "no-observed-adverse-effect levels" Regulatory Toxicology and Pharmacology. 11:1990;314-330.
55. Lu F. C. 1990. Immunotoxicologie. In Toxicologie. Données générales, procédures d'évaluation, organes cibles, évaluation du risque. pp. 145-156. Ed. Masson. Paris.
56. Luster M. I., Portier C., Pait D. G., Rosenthal G. J., Germolec D. R., Corsini E., et al. Risk assessment in immunotoxicology. II. Relationships between immune and host resistance tests. Fundamental and Applied Toxicology. 21:1993;71-82.
57. Luster M. I., Portier C., Pait D. G., White K. L. J., Gennings C., Munson A. E., Rosenthal G. J. Risk assessment in immunotoxicology. I. Sensitivity and predictability of immune tests. Fundamental and Applied Toxicology. 18:1992;200-210.
58. Madsen C. (1995) Gastrointestinal tract allergy and intolerance. In Allergenic Hypersensitivities Induced by Chemicals, ed. J. G. Vos, M. Younes and E. Smith, pp. 301-314. CRC Press, Boca Raton, FL.
59. Mäkelä S., et al. Dietary estrogens act through estrogen receptor-mediated processes and show no antiestrogenicity in cultured breast cancer cells. Environmental Health Perspectives. 102:1994;572-578.
60. Markaverich B. M., Roberts R. R., Alejandro M. A., Johnson G. A., Middleditch B. S., Clark J. H. Bioflavonoids interaction with rat uterine type II binding sites and cell growth inhibition. Journal of Steroid Biochemistry. 30:1978;71-78.
61. Metcalfe D. D., Astwood J. D., Townsend R., Sampson H. A., Taylor S. L., Fuchs R. L. Assessment of the allergenic potential of foods derived from genetically engineered crop plants. Critical Reviews in Food Science and Nutrition. 36:(Suppl.):1996;S165-S186.
62. Miksicek R. J. Commonly occurring plant flavonoids have estrogenic activity. Molecular Endocrinology. 44:1993;37-43.
63. Miller W. R. (1996) Medical intelligence unit: estrogens and breast cancer. RG Landes Company and Chapman & Hall, Austin, TX. ISBN 0-412-10371-0.
64. Moolenaar R. J. Carcinogen risk assessment. Regulatory Toxicology and Pharmacology. 20:1994;302-336.
65. Moore R. W., Jefcoate C. R., Peterson R. E. 2,3,7,8-Tetrachlorodibenzo-p-dioxin inhibits steroidogenesis in the rat testis by inhibiting the mobilization of cholesterol to cytochrome P450. Toxicology and Applied Pharmacology. 109:1991;85-97.
66. Morita K., Ono T., Shimakawa H. Inhibition of testosterone biosynthesis in testicular microsomes by various imidazole drugs. Comparative study with ketoconazole. Journal of Pharmacobiodynamics. 13:1990;336-343.
67. Munro I. C. Safety assessment procedures for indirect food additives: An overview. Report of a workshop. Regulatory Toxicology and Pharmacology. 12:1990;2-12.
68. Munro I. C., Ford R. A., Kennepohl E., Sprenger J. G. Correlation of structural class with No-Observed-Effect-Levels: a proposal for establishing a threshold of concern. Food and Chemical Toxicology. 34:1996;829-867.
69. Munro I. C. and Kroes R. (1998) Application of a threshold of toxicological concern in the safety evaluation of certain flavouring substances. Safety evaluation of certain food additives and contaminants (Annex 5). WHO Food Additives Series No. 40.
70. Munro I. C., Kennepohl E., Kroes R. Application of a threshold of toxicological concern in the safety evaluation of certain flavouring substances. Food and Chemical Toxicology. 37:1999;207-232.
71. NRC (1996) Carcinogens and Anticarcinogens in the Human Diet. National Research Council. National Academy Press, Washington, DC.
72. Neubert D. Vulnerability of the endocrine system to xenobiotic influence. Regulatory Toxicology and Pharmacology. 26:1997;9-26.
73. NTIS (1991) Pesticide Assessment Guidelines, Subdivision F, Hazard Evaluation: Human and Domestic Animals, Addendum 10: Neurotoxicity. Series 81, 82 and 83. US-EPA 540/09-91-123. PB91-154617.
74. NTP (1989) NTP Technical Report on the perinatal toxicity and carcinogenicity studies of ethylene thiourea (CAS No. 96-45-7) in F/344 rats and B6C3F1 mice (feed studies). National Toxicology Program.
75. O'Connor J. C., Cook J. C., Craven S. C., Van Pelt C. S., Obourn J. D. An in vivo battery for identifying endocrine modulators that are estrogenic or dopamine regulators. Fundamental and Applied Toxicology. 33:1996;182-195.
76. Odum J., Tittensor S., Ashby J. Limitations of the MCF-7 cell proliferation assay for detecting xenobiotic oestrogens. Toxicology in Vitro. 12:1998;273-278.
77. Ramamoorthy K., Wang F., Chen I. C., Norris J. D., McDonnel D. P., Leonard L. S., et al. Estrogenic activity of a dieldrin/toxaphen mixture in the mouse uterus, MCF-7 human breast cancer cells, and yeast-based estrogen receptor assays: no apparent synergism. Endocrinology. 138:1997;1520-1527.
78. Reck G., Noss U., Breckwoldt M. Acta Endocrinologica. 90:1979;519.
79. Reed M. J. (1983) Hormones in Blood, ed. C. H. Gray and V. H. T. James, Vol. 4. 3rd edn, pp. 318. Academic Press, London.
80. Reel J. R., Lamb J. C., Neal B. H. Survey and assessment of mammalian estrogen biological assays for hazard characterisation. Fundamental and Applied Toxicology. 34:1997;288-305.
81. Renwick A. G. Data-derived safety factors for the evaluation of food additives and environmental contaminants. Food Additives and Contaminants. 10:1993;275-305.
82. Roberts D. W. and Chapman J. R. (1981) Concepts essential to the assessment of toxicity to the developing immune system. In Developmental Toxicology, ed. C. A. Kimmel and J. Buelke-Sam, pp. 167-190. Raven Press, New York.
83. Roitt I., Brostoff J. and Male D. (1993) Immunologie, 3rd edn. De Boeck Université
84. Rudel R. Predicting health effects of exposures to compounds with estrogenic activity: Methodological issues. Environmental Health Perspectives. 105:(Suppl. 3):1997;655-663.
85. Rulis A. M. (1986) De Minimis and the threshold of regulation. In Food Protection Technology, ed. C. W. Felix, pp. 29-37. Lewis Publishers, Chelsea, MI.
86. Rulis A. M. (1989) Establishing a threshold of concern. In Risk Assessment in Setting National Priorities, ed. J. J. Bonin and D. E. Stevenson, Vol. 7, pp. 271-278. Plenum Press, New York.
87. Safe S. H. Environmental and dietary estrogens and human health: is there a problem? Environmental Health Perspectives. 103:1995;346-351.
88. Saunders P. T. K., Maguire S. M., Gaughan J., Millar M. R. Expression of estrogen receptor beta (ERb) in multiple rat tissues visualised by immunohistochemistry. Journal of Endocrinology. 154:1997;R13-R16.
89. SCF (Scientific Committee for Food) (1996) Opinion on Response to Request from the Commission for SCF Opinion on the Scientific Basis of the Concept of Threshold of Regulation in Relation to Food Contact Materials. Annex VII to Document III/5557/96. European Commission, Brussels.
90. Sharpe R. M., Skakkebaek N. E. Are estrogens involved in falling sperm count and disorders of the male reproductive tract? Lancet. 341:1993;1392-1395.
91. Shelby M. D., Newbold R. R., Tully D. B., Chae K., Davis V. L. Assessing environmental chemicals for estrogenicity using a combination of in vitro and in vivo assays. Environmental Health Perspectives. 104:1996;1296-1300.
92. Soto A. M., Chung K. L., Sonnenschein C. The pesticides Endosulfan, Toxaphene, and Dieldrin have estrogenic effects on human estrogen-sensitive cells. Environmental Health Perspectives. 102:1994;380-383.
93. Soto A., Sonnenschein C., Chung K. L., Fernandez M. F., Olea N., Olea Serrano F. The E-screen assay as a tool to identify estrogens: an update on estrogenic environmental pollutants. Environmental Health Perspectives. 103:(Suppl. 7):1995;113-122.
94. Stanworth D. R. (1987) Mechanisms of pseudo-allergy. In Immunotoxicology, ed. A. Berlin, J. Dean, M. H. Draper, E. M. B. Smith and F. Spreafico. pp. 426-442. Martinus Nijhoff Publishers, Dordrecht.
95. Stevens J. T., Tobia A., Lamb J. C., Tellone C., O'Neal F. FIFRA Subdivision F Testing Guidelines: are these tests adequate to detect potential hormonal activity for crop protection chemicals? Journal of Toxicology and Environmental Health. 50:1997;415-431.
96. Taylor S. L., Dormedy E. S. The role of flavoring substances in food allergy and intolerance. Advances in Food Nutrition Research. 42:1998;1-44.
97. Taylor S. L., Lemanske R. F. J., Bush R. K., Busse W. W. Food allergens: structure and immunologic properties. Annals of Allergy. 59:1987;93-99.
98. Tennant R. W., Ashby J. Classification according to chemical structure, mutagenicity to Salmonella and level of carcinogenicity of a further 39 chemicals tested for carcinogenicity by the US National Toxicology Program. Mutation Research. 257:1991;209-227.
99. Trizio D., Basketter D. A., Botham P. A., Graepel P. H., Lambré C., Magda S. J., Pal T. M., Riley A. T., Ronneberger H., Van Sittert N. J., Bontinck W. J. Identification of immunotoxic effects of chemicals and assessment of their relevance to man. Food and Chemical Toxicology. 26:1988;527-539.
100. Ulbrich B., Palmer A. K. Neurobehavioral aspects of developmental toxicity testing. Environmental Health Perspectives. 104:(Suppl. 2):1996;407-412.
101. Unnérus H. A. Acta Endocrinologica. 91:(Suppl.):1979;266.
102. Vanden Bossche H. (1985) Biochemical targets for antifundal azole derivatives: hypothesis on the mode of action. In Current Topics in Medical Mycology, ed. M. R. McGinnis. Vol. 1. pp. 313-351.
103. Verdeal K., Ryan D. S. Naturally-occurring estrogens in plant foodstuffs - a review. Journal of Food Protection. 42:1979;577-583.
104. vom Saal F.S., Nagel S. C., Palanza P., Boechler M., Parmigiani S., Welshons W. V. Estrogenic pesticides: binding relative to estradiol in MCF-7 cells and effects of exposure during foetal life on subsequent territorial behaviour in male mice. Toxicology Letters. 77:1995;343-350.
105. Vorhees C. V. Reliability, sensitivity and validity of behavioural indices of neurotoxicity. Neurotoxicology and Teratology. 9:1987;445-464.
106. Weil C. S., McCollister D. D. Safety evaluation of chemicals. Relationship between short- and long-term feeding studies in designing an effective toxicity test. Agricultural and Food Chemistry. 11:1963;486-491.
107. WHO (1987) Principles For The Safety Assessment of Food Additives and Contaminants in Food. WHO Environmental Health Criteria. World Health Organization (WHO), International Program on Chemical Safety (IPCS), in cooperation with the Joint FAO (Food and Agriculture Organization of the United Nations)/WHO Expert Committee on Food Additives (JECFA), Geneva, Switzerland, Environmental Health Criteria No. 70.
108. Winter C. K. Dietary pesticide risk assessment. Reviews of Environmental Contamination and Toxicology. 127:1992;23-67.
109. Wolff M. S., Toniolo P. G., Lee E. W., Rivera M., Dubin N. Blood levels of organochlorine residues and risk of breast cancer. Journal of the National Cancer Institute. 85:1993;648-652.
110. Wüthrich B. (1995) Position paper of the EAACI. In Proceedings of the XVI European Congress of Allergology and Clinical Immunology (EAACI), Madrid, Spain, 25-30 June 1995. pp. 859.
111. Ziegler J. How endogenous estrogens work. Journal of the National Cancer Institute. 89:1997;1186.