Alternate Methods for Integrated Evaluation of Toxicity and Risk Assessment

  • Laila A. Moustafa
Part of the Environmental Science Research book series (ESRH, volume 31)

Abstract

Animal bioassays by themselves can yield ambiguous results, especially in relation to human risk assessment. Three major alternates are proposed for integration in toxicology evaluations. The first is mathematical modeling and expression, viz. , statistical and quantitative structure/activity relationship (QSAR). Mathematical modeling can run indefinitely after animal experiments have terminated, and can serve as a powerful adjunct to animal experiments. Quantum mechanical analysis (QMA) can help researchers to study, on the molecular level, the interactions of chemicals and the body and to understand and predict side effects. QSAR assumes that a functional dependence exists between the observed biological response and certain physiological properties of molecules. With QMA implementation in QSAR, one can obtain reactivity characteristics in order to relate molecular structure to the observed biological activity. Stereology (morphometry) can be used to attach quantitative values to complex biological structures identified in light and electron micrographs. By integrating structural/functional data one expects to pinpoint the specific cellular responses to one or several chemicals, and even to predict genetic events from cytoplasmic changes. The second alternate is a battery of in vitro toxicity tests. For example, plasticity of synapse formation with cultured nerve cells should yield rich dividends when coupled with monoclonal antibody and recombinant DNA technology. Monoclonal antibody technology, when applied to studying nerve cell biochemistry, should be extremely useful in identifying the structure of various surface components on nerve cells. Recombinant DNA technology is likely to yield important information with regard to specific gene expression. An application of in vitro systems to teratogenecity testing has been actively pursued. The third alternate is the use of plants. Plant systems show promise for immediate use in laboratory short-term bioassays for toxicity evaluation of specific chemicals or chemical mixtures. For testing under field conditions, few test organisms offer the advantages provided by plants.

Keywords

Corn Chlorophyll Cadmium Cellular Respiration Germinal 

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References

  1. 1.
    Asher, I. M. , and C. Zervos, Eds. (1977) Structural Correlates of Carcinogenesis and Mutagenesis. A Guide to Testing Priorities?, Proceedings of 2nd FDA Office of Science Summer Symposium, 31 August - 2 September, 1977.Google Scholar
  2. 2.
    Baur, H. , S. Kasperek, and E. Pfaff (1975) Criteria of viability of isolated liver cells.Z. Physiol. Chem. 356: 827 – 838.Google Scholar
  3. 3.
    Blouin, A. , R. P. Bolender, and E. R. Weibel (1977) Distribution of organelles and membranes between hepatocytes and nonhepatocytes in the rat liver parenchyma. A stereological study.J. Cell Biol. 72 (2): 441 – 445.CrossRefGoogle Scholar
  4. 4.
    Bolender, R. P. (1974) Stereological analysis of the guinea pig pancreas. I. Analytical model and quantitative description of nonstimulated pancreatic exocrine cells.J. Cell Biol. 61: 269 – 289.CrossRefGoogle Scholar
  5. 5.
    Bolender, R. P. (1981) Stereology: Applications to pharmacology.Ann. Rev. Pharmacol. Toxicol. 21: 549 – 573.CrossRefGoogle Scholar
  6. 6.
    Bolender, R. P. (1982) Stereology and its uses in cell biology.Ann. N. Y. Acad. Sci. 383: 1 – 16.CrossRefADSGoogle Scholar
  7. 7.
    Bolender, R. P. , D. Baumgartner, G. Losa, D. Muellener and E. R. Weibel (1978) Integrated stereological and biochemical studies on hepatocytic membranes. I. Methods and membrane recoveries.J. Cell Biol. 77: 565 – 583.CrossRefGoogle Scholar
  8. 8.
    Cammarata, A. , and S. T. Yau (1970) Predictability of correlations between in vitro tetracycline potencies and substituent indices.J. Med. Chem. 13: 93 – 97.CrossRefGoogle Scholar
  9. 9.
    Chu, K. C. , R. J. Feldmanf M. B. Shapiro, G. F. Hazard, and R. I. Geran (1975) Pattern recognition and structure–activity relationship studies. Computer-assisted prediction of antitumor activity in structurally diverse drugs in an experimental mouse brain tumor system.J. Med. Chem. 18 (6): 539 – 545.CrossRefGoogle Scholar
  10. 10.
    De Ritis, G. , Z. M. Falchuk, and J. S. Trier (1975) Differentiation and maturation of cultured fetal rat jejunum.Develop. Biol. 45: 304 – 313.Google Scholar
  11. 11.
    De Ritis, G. , P. Occorsio, S. Auricchio, F. Gramenzi, G. Morisi, and V. Silano (1979) Toxicity of wheat flour proteins and protein–derived peptides for in vitro developing intestine from rat fetus.Pediat. Res. 13: 1255 – 1261.Google Scholar
  12. 12.
    Dettoff, R. T. , and F. N. Rhines, Eds. (1968)Quantitative Microscopy, McGraw–Hill Book Company, New York.Google Scholar
  13. 13.
    Diamond, B. , and M. D. Scharff (1982) Monoclonal antibodies.J. Am. Med. Assoc. 249: 3165 – 3169.CrossRefGoogle Scholar
  14. 14.
    Dove, S. , R. Franke, O. L. Mndshojan, W. A. Schkuljev, and L. W. Chashakjan (1979) Discriminant–analytical investigation on the structural dependence of hyperglycemic and hypoglycemic activity in a series of substituted o– toluenesulfonylthioureas and o–toluene–sulfonylureas.J. Med. Chem. 22 (1): 90 – 95.CrossRefGoogle Scholar
  15. 15.
    Dunn, W. J. , III, and S. Wold (1978) A structure– carcinogenicity study of 4-nitroquinoline 1-oxides using the SIMCA method of pattern recognition.J. Med. Chem. 21: 1001 – 1007.CrossRefGoogle Scholar
  16. 16.
    Dunn, W. J. , III, M. J. Greenberg, and S. S. Callejas (1976) Use of cluster analysis in the development of structure–activity relations for antitumor triazenes.J. Med. Chem. 19: 1299 – 1301.CrossRefGoogle Scholar
  17. 17.
    Dunn, W. J. , III, S. Wbld, and Y. C. Martin (1978) Structure- activity study of B-adrenergic agents using the SIMCA method of pattern recognition.J. Med. Chem. 21: 922 – 930.CrossRefGoogle Scholar
  18. 18.
    EHP (1978) Higher plants as monitors of environmental mutagens-workshop, January 1978.Environm. Health Persp. 27: 1 – 206.Google Scholar
  19. 19.
    EHP (1981) Pollen systems to detect biological activity of environmental pollutants. Proceedings of conference.Environm. Health Persp. 37: 1 – 200.CrossRefGoogle Scholar
  20. 20.
    Elias, P. S. (1978) General Guidelines for the Toxicological Evaluation of Chemical Substances, Commission of the European Communities, Doc. No. V/F/l/78/26, Luxembourg, April 1978.Google Scholar
  21. 21.
    Feder, J. , and W. R. Tolbert (1983) The large-scale cultivation of mammalian cells.Scientific American248 (1): 36 – 43.CrossRefGoogle Scholar
  22. 22.
    Fedoroff, S. (1977) Primary cultures, cell lines and cell strains: Terminology and characteristics, InCell, Tissue and Organ Cultures in Neurobiology, S. Fedoroff and L. Hertz, Eds. , Academic Press, New York, pp. 265.Google Scholar
  23. 23.
    Free, S. M. , Jr. , and J. W. Wilson (1964) A mathematical contribution to structure-activity studies.J. Med. Chem. 7: 395 – 399.CrossRefGoogle Scholar
  24. 24.
    Fujita, T. , and T. Ban (1971) Structure–activity study of phenethylamines as substrates of biosynthetic enzymes of sympathetic transmitters.J. Med. Chem. 14: 148 – 152.CrossRefGoogle Scholar
  25. 25.
    Giller, E. L. , X. O. Breakefield, C. N. Christian, E. A. Neale, and P. G. Nelson (1975) Expression of neuronal characteristics in culture: Scxne pros and cons of primary cultures and continuous cell lines, InGolgi Centennial Symposium, M. Santini, Ed. , Raven Press, New York, p. 603.Google Scholar
  26. 26.
    Green, J. P. , and H. Vfeinstein (1981) Quantum mechanics can account for the affinities of drugs and receptors.The Sciences(September 1981 ) 21: 27 – 29.Google Scholar
  27. 27.
    Griesemer, R. (1981) Whole animal methods for toxicity testing, InTrends in Bioassay Methodology, In Vivo, In Vitro and Mathematical Approaches Symposium, Organized by National Institutes of Health and National Toxicology Program, 18–20 February 1981. NIH Publication No. 82 – 2382, Washington, D. C.Google Scholar
  28. 28.
    Hansch, C. (1971) Quantitative structure–activity relationships in drug design. InDrug Design(1), E. J. Ariens, Ed. , Volume 11, part 1 of Medicinal Chemistry: A Series of Monographs, George DeStevens, Gen. Ed. , Academic Press, New York, pp. 271 – 337.Google Scholar
  29. 29.
    Hansch, C. , A. Leo, S. H. Unger, K. H. Kim, D. Nikaitani, and E. Lien (1973) “Aromatic” substituent constants for structure-activity correlations.J. Med. Chem. 16:1207–1216.Google Scholar
  30. 30.
    Hathway, D. E. , and G. F. Kolar (1980) Mechanisms of reaction between ultimate chemical carcinogens and nucleic acid.Chem. Soc. Rev. 9 (2): 241 – 264.CrossRefGoogle Scholar
  31. 31.
    Hirota, N. , and G. M. Williams (1979) The sensitivity and heterogeneity of histochemical markers for altered foci involved in liver carcinogenesis.Amer. J. Pathology95 (2): 317 – 324.Google Scholar
  32. 32.
    Iozzo, R. V. , R. P. Bolender, and T. N. Wight (1982) Proteoglycan changes in the intercellular matrix of human colon carcinoma. An integrated biochemical and stereological analysis.Lab. Invest. 47 (2): 124 – 138.Google Scholar
  33. 33.
    IRPTC (1982) International Register of Potentially Toxic Chemicals, Bulletin, Vol. 5, No. 2, October 1982.Google Scholar
  34. 34.
    Kimmel, G. L. , K. Smith, D. M. Kochhar, and R. M. Pratt (1982) Overview of in vitro teratogenicity testing: Aspects of validation and application to screening.Teratog. Carcinog. Mutagen. 2: 221 – 229.Google Scholar
  35. 35.
    Kowalski, B. R. , and C. F. Bender (1974) The application of pattern recognition to screening prospective anticancer drugs. Adenocarcinoma 755 biological activity test.J. Amer. Chem. Soc. 96: 916 – 918.CrossRefGoogle Scholar
  36. 36.
    Losa, G. , E. R. Weibel, and R. P. Bolender (1978) Integrated stereological and biochemical studies on hepatocytic membranes. III. Relative surface of endoplasmic reticulum membranes in microsomal fractions estimated on freeze fracture preparations.J. Cell Biol. 78: 289 – 308.CrossRefGoogle Scholar
  37. 37.
    Martin, Y. C. (1974) Proceedings: Extra thermodynamic approach to drug design (supp. ), InCancer Chemother. Rep, part 2, 4 (4): 35 – 36.Google Scholar
  38. 38.
    Martin, Y. C. (1978) Quantitative drug design, a critical introduction, InMedicinal Research Series, Volume 8, G. L. Grunewald, Ed. , Marcel Dekker, Inc. , New York.Google Scholar
  39. 39.
    Martin, Y. C. , J. B. Holland, C. H. Jarboe, and N. Plotnikov (1974) Discriminant analysis of the relationship between physical properties and the inhibition of monoamine oxidase by aminotetralins and aminoindans.J. Med. Chem. 17: 409 – 413.CrossRefGoogle Scholar
  40. 40.
    Maugh, T. H. (1978) Chemicals: How many are there?Science199: 152.CrossRefADSGoogle Scholar
  41. 41.
    Maugh, T. H. (1983) Chemicals: How many are there?Science220: 293.ADSGoogle Scholar
  42. 42.
    Meyler, L. , and A. Herscheimer, Eds. (1972) Side Effects of Drugs, Volume 7:A Survey of Unwanted Effects of Drugs, Reported in 1968–1971 Excerpta Medica Amsterdam.Google Scholar
  43. 43.
    Miller, J. A. (1970) Carcinogenesis by chemicals: An overview. The G. H. A. Clowes Memorial Lecture.Cancer Res. 30: 559 – 576.Google Scholar
  44. 44.
    Moustafa, L. A. (1976) New observations on rabbit blastocysts afterin vitroexposure to thalidomide—sane correlated SEM and TEM studies, InScanning Electron Microscopy1976, part VI, G. Johari, and R. P. Becker, Eds. . , IIT Research Institute, Chicago, pp. 385 – 391.Google Scholar
  45. 45.
    Moustafa, L. A. , and J. Hahn (1978) Untersuchungen uber die Brauchbarkeit der Kultivierung von befruchteten Eizellen in Mini–Pailletten.Zuchthygiene13: 61 – 67.CrossRefGoogle Scholar
  46. 46.
    Nardone, R. M. (1977) Toxicity testing in vitro, In Growth,Nutrition and Metabolism of Cells in Culture, Vol. 3. , G. H. Rothblat, and V. J. Cristofalo, Eds. , Academic Press, New York, p. 471.Google Scholar
  47. 47.
    NAS (1975)Principles for Evaluating Chemicals in the Environment, National Academy of Sciences, Washington, D. C.Google Scholar
  48. 48.
    Nixon, G. A. , C. A. Tyson, and W. C. Wertz (1975) Interspecies comparisons of skin irritancy.Toxicol. Appl. Pharmacol. 31 (3): 481 – 490.Google Scholar
  49. 49.
    NTP (1982) National Toxicology Program: Fiscal Year 1983 Annual Plan, US Department of Health and Human Services, Public Health Service.Google Scholar
  50. 50.
    Osman, R. , H. Weinstein, and J. P. Green (1979) Parameters and methods quantitative structure–activity relationships, InComputer-Assisted Drug Design, E. C. Olson, and R. E. Christofferson, Eds. , ACS Symposium Series No. 112, pp. 21 – 77.Google Scholar
  51. 51.
    Osman, R. , H. Weinstein, and S. Topiol (1981) Models for active sites of metalloenzymes. II. Interactions with a model substrate. Ann. N. Y. Acad. Sci. 367: 356 – 369.CrossRefADSGoogle Scholar
  52. 52.
    Pieri, C. , I. Zs. Nagy, C. Mazzufferi, and C. Giuli (1975a) The aging of rat liver as revealed by electron microscopy. Morphometry - I. Basic parameters.Exp. Gerontol. 10 (5): 291 – 304.Google Scholar
  53. 53.
    Pieri, C. , I. Zs. Nagy, G. Mazzufferi, and C. Giuli (1975b) The aging of rat liver as revealed by electron microscopy. II. Parameters of regenerated old liver.Exp. Gerontol. 10 (6): 341 – 349.Google Scholar
  54. 54.
    Prakash, G. , and E. M. Hodnett (1978) Discriminant analysis and structure–activity relationships. 1. Naphthoquinones.J. Med. Chem. 21: 369 – 374.CrossRefGoogle Scholar
  55. 55.
    Pratt, R. M. , R. I. Grove, and W. D. Willis (1982) Prescreening for environmental teratogens using cultured mesenchymal cells from the human embryonic palate.Teratog. Carcinog. Mutagen. 2: 313 – 318.Google Scholar
  56. 56.
    Price, C. C. (1958) Fundamental mechanisms of alkylation.Ann. N. Y. Acad. Sci. 68: 663 – 668.CrossRefADSGoogle Scholar
  57. 57.
    Price, C. C. , G. M. Gaucher, P. Koneru, R. Shibakawa, J. R. Sowa, and M. Yamaguchi (1969) Mechanism of action of alkylating agents.Ann. N. Y. Acad. Sci. 163: 593 – 600.CrossRefADSGoogle Scholar
  58. 57.
    Price, C. C. , G. M. Gaucher, P. Koneru, R. Shibakawa, J. R. Sowa, and M. Yamaguchi (1969) Mechanism of action of alkylating agents.Ann. N. Y. Acad. Sci. 163: 593 – 600.CrossRefADSGoogle Scholar
  59. 59.
    Sato, G. , Ed. (1973)Tissue Culture of the Nervous System – Current Topics in Neurobiology, Volume 1, Plenum Press, New York.Google Scholar
  60. 60.
    Science (1983) Biotechnology issue.Science219 (4585): 611 – 747.Google Scholar
  61. 61.
    Sharrat, M. (1977) Objective Evaluation from Animal Data of he Risks to Human Health from Chemical Agents, Commission of the European Communities, Doc. No. 2144/77e, Luxembourg, June 1977.Google Scholar
  62. 62.
    Soltzberg, L. J. , and C. L. Wilkins (1977) Molecular transforms: A potential tool for structure–activity studies.J. Amer. Chem. Soc. 99: 439 – 443.CrossRefGoogle Scholar
  63. 63.
    Stammati, A. P. , V. Silano, and F. Zucco (1981) Toxicology investigations with cell culture systems.Toxicology20: 91 – 153.CrossRefGoogle Scholar
  64. 64.
    Stewart, R. D. , J. E. Peterson, P. E. Newton, C. L. Lake, M. J. Hosko, A. J. Lebrun, and G. M. Lawton (1974) Experimental human exposure to propylene glycol dinitrate.Toxicol. Appl. Pharmaco. 30 (3): 377 – 395.Google Scholar
  65. 65.
    Stuper, A. J. , and P. C. Jurs (1975) Classification of psychotropic drugs as sedatives or tranquilizers using pattern recognition techniques.J. Amer. Chan. Soc. 97(l)sl82–187.Google Scholar
  66. 66.
    Szabo, K. T. , M. E. DiFebbo, Y. J. Kang, A. K. Palmer, and R. L. Brent (1975) Comparative embryotoxicity and teratogenicity of various tranquilizing agents in mice, rats, rabbits, and rhesus monkeys. Fourteenth Annual Meeting of the Society of Toxicology, Williamsburg, Virginia, 9–13 March 1975. Abstract in:Toxicol. Appl. Pharmacol. 33:124.Google Scholar
  67. 67.
    Ting, K. H. , R. C. T. Lee, G. W. A. Milne, H. Shapiro, and A. M. Gaurino (1973) Applications of artificial intelligence: Relationships between mass spectra and pharmacological activity of drugs.Science180: 417 – 420.CrossRefADSGoogle Scholar
  68. 68.
    Underwood, E. E. (1970)Quantitative Stereology, Addison-Wesley Publishing Company, Reading, Massachusetts.Google Scholar
  69. 69.
    Weibel, E. R. (1979) Stereological Methods. Volume 1:Stereological Methodsfor Biological Morphometry, Academic Press, London.Google Scholar
  70. 70.
    Weibel, E. R. (1980)Stereological Methods. Volume 2: Theoretical Foundations, Academic Press, London.Google Scholar
  71. 71.
    Weinstein, H. , R. Osman, and J. P. Green (1979) The molecular basis of structure-activity relationships: Quantum chemical recognition mechanisms in drug-receptor interactions, InComputer-Assisted Drug Design, ACS Symposium Series 112, E. O. Olson, and R. E. Christofferson, Eds. , American Chemical Society, Washington, D. C. , pp. 161 – 187.Google Scholar
  72. 72.
    Weinstein, H. , S. Topiol, and R. Osman (1981a) On the relation between charge redistribution andintermolecular forcesin models for molecular interactions in biology, In Intermolecular Forces, B. Pullman, Ed. , D. Reidel Publishing Company, pp. 383 – 396.Google Scholar
  73. 73.
    Weinstein, H. , R. Osman, S. Topiol, and J. P. Green (1981b) Quantum chemical studies on molecular determinants for drug action.Ann. N. Y. Acad. Sci. 367: 434 – 451.CrossRefADSGoogle Scholar
  74. 74.
    Weisburger, J. H. , and G. M. Williams (1981) Carcinogen testing: Current problems and new approaches.Science214: 401 – 407.CrossRefADSGoogle Scholar
  75. 75.
    Williams, M. A. (1977) Quantitative methods in biology, InPractical Methods in Electron Microscopy, Vol. 6, A. M. Glauert, Ed. , North Holland Publishing Company, Amsterdam.Google Scholar
  76. 76.
    Wininger, M. T. , J. M. Lavoie, and W. D. Ross (1982)In vitrosub-lethal toxicity indicated by changes in cellular energy metabolite levels. 33rd Annual Meeting of the Tissue Culture Association, 6–10 June 1982, San Diego.Google Scholar
  77. 77.
    Yoneda, T. , and R. M. Pratt (1981) Mesenchymal cells from the human embryonic palate are highly responsive to EGF.Science213: 563 – 565.CrossRefADSGoogle Scholar

Copyright information

© Plenum Press, New York 1984

Authors and Affiliations

  • Laila A. Moustafa
    • 1
  1. 1.International Programme on Chemical Safety, Interregional Research UnitWorld Health OrganizationUSA

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