European Journal of Epidemiology

, Volume 25, Issue 8, pp 539–546 | Cite as

The scientific assessment of combined effects of risk factors: different approaches in experimental biosciences and epidemiology

Methods

Abstract

The analysis of combined effects of substances or risk factors has been a subject to science for more than a century. With different goals, combined effect analysis was addressed in almost all experimental biosciences. The major theoretical foundation can be traced back to two distinct origins. First, to the work by the pharmacologist Loewe on the concept of concentration additivity and second to the biometrician Bliss and the concept of independent action. In the search for a general solution and a unified terminology the interrelations of the concepts have extensively been studied and experimental findings reviewed. Meanwhile there seems to be consensus in experimental sciences that each concept has its role in predicting combined effect of agents and both are used for hazard und risk management. In contrast, epidemiologists describe combined effects mainly in terms of interactions in regression models. Although this approach started from a probabilistic model equivalent to the concept of independent action this origin is rarely acknowledged and effect summation is usually the preferred concept nowadays. Obscure biological meaning, the scale dependency of interaction terms as well as unavoidable residual confounding are taken as reasons why no new insights in combined effect analysis are likely to occur from epidemiology. In this paper we sketch the history of ideas and the state of the arts in combined effect analysis. We point to differences and common grounds in experimental biosciences and epidemiology.

Keywords

Combined effect analysis Synergism Antagonism Additivity Independent action 

References

  1. 1.
    Calabrese EJ. Multiple chemical interaction. Chesia: Lewis Publishers; 1991.Google Scholar
  2. 2.
    Pöch G. Combined effects of drugs and toxic agents. Modern evaluation intheory and practice. Wien: Springer; 1993.Google Scholar
  3. 3.
    Chou TC. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev. 2006;58:621–81.CrossRefPubMedGoogle Scholar
  4. 4.
    Berenbaum MC. The expected effect of a combination of agents: the general solution. J Theor Biol. 1985;114:413–31.CrossRefPubMedGoogle Scholar
  5. 5.
    Greco W, Unkelbach HD, Pöch G, Sühnel J, Kundi M, Boedeker W. Consensus on concepts and terminology for combined action assessment: the Saariselkä agreement. Arch Complex Environ Stud. 1992;4(3):65–9.Google Scholar
  6. 6.
    Faust M, Altenburger R, Boedeker W, Grimme LH. Algal toxicity of binary combinations of pesticide. Bull Environ Contam Toxicol. 1994;53:134–41.CrossRefPubMedGoogle Scholar
  7. 7.
    Faust M, Altenburger R, Backhaus T, Blanck H, Boedeker W, Gramatica P, Hamer V, Scholze M, Vighi M, Grimme LH. Joint algal toxicity of 16 dissimilarly acting chemicals is predictable by the concept of independent action. Aquat Toxicol. 2003;63(1):43–63.CrossRefPubMedGoogle Scholar
  8. 8.
    Silva E, Rajapakse N, Kortenkamp A. Something from “nothing”—eight weak estrogenic chemicals combined at concentrations below NOECs produce significant mixture effects. Environ Sci Technol. 2002;36(8):1751–6.CrossRefPubMedGoogle Scholar
  9. 9.
    Backhaus T, Faust M, Scholze M, Gramatica P, Vighi M, Grimme LH. Joint algal toxicity of phenylurea herbicides is equally predictable by concentration addition and independent action. Environ Toxicol Chem. 2004;23(2):258–64.CrossRefPubMedGoogle Scholar
  10. 10.
    Altenburger R, Boedeker W, Faust M, Grimme LH. Regulations for combined effects of pollutants: consequences from risk assessment in aquatic toxicology. Food Chem Toxicol. 1996;34:1155–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Altenburger R, Greco WR. Extrapolation concepts for dealing with multiple contamination in environmental risk assessment. Integr Environ Assess Manage. 2009;5:62–8.CrossRefGoogle Scholar
  12. 12.
    Kortenkamp A, Backhaus T, Faust M. State of the art report on mixture toxicity, report to the directorate general for the environment, EU commission. 2009. http://ec.europa.eu/environment/chemicals/pdf/report_Mixture%20toxicity.pdf (last accessed 2010-04-21).
  13. 13.
    Kaufman JS. Interaction reaction. Epidemiology. 2009;20(2):159–60.CrossRefPubMedGoogle Scholar
  14. 14.
    Knol MJ, Egger M, Scott P, Geerlings MI, Vandenbroucke JP. When one depends on the other. Reporting of interaction in case-control and cohort studies. Epidemiology. 2009;20(2):161–6.CrossRefPubMedGoogle Scholar
  15. 15.
    Greenland S. interactions in epidemiology: relevance, identification, and estimation. Epidemiology. 2009;20(1):14–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Unkelbach HD, Wolf T. Drug combinations—concepts and terminology. Arzneim Forsch. 1984;34 II(9):935–8.Google Scholar
  17. 17.
    Loewe S, Muischnek H. Über Kombinationswirkungen I. Mitteilung: Hilfsmittel der Fragestellung. Naunyn-Schmiedebergs Arch Exp Pathol u Pharmakol. 1926;114:313–26.CrossRefGoogle Scholar
  18. 18.
    Bliss CI. The toxicity of poisons applied jointly. Ann Appl Biol. 1939;26:585–615.CrossRefGoogle Scholar
  19. 19.
    Finney DJ. The analysis of toxicity tests on mixtures of poisons. Ann Apll Biol. 1942;29:82–94.CrossRefGoogle Scholar
  20. 20.
    Plackett RL, Hewlett PS. Statistical aspects of the independent joint action of poisons particularly insecticides. I. The toxicity of a mixture of poisons. Ann Appl Biol. 1948;35:347–58.PubMedGoogle Scholar
  21. 21.
    Ashford JR. Quantal responses to mixtures of poisons under conditions of simple similar action. The analysis of uncontrolled data. Biometrika. 1958;45:74–88.Google Scholar
  22. 22.
    Marking LL. Toxicity of chemical mixtures. In: Rand GM, Petrocelli SR, editors. Fundamentals of aquatic toxicology. Washington: Hemisphere Publishing Corporation; 1977.Google Scholar
  23. 23.
    Könemann H. Quantitative structure-activity relationships in fish toxicity studies Part 1: relationship for 50 industrial pollutants. Toxicology. 1980;19:209–21.CrossRefGoogle Scholar
  24. 24.
    Anderson PD, Weber LJ. The toxicity to aquatic populations of mixtures containing certain heavy metals. Proc Int Conf Heavy Metals Environ. 1975;2:933–53.Google Scholar
  25. 25.
    Morse PM. Some comments on the assessment of joint action in herbicide mixtures. Weed Sci. 1978;26(1):58–71.Google Scholar
  26. 26.
    Berenbaum MC. Criteria for Analysing Interactions between biologically active agents. Adv Cancer Res. 1981;35:269–335.CrossRefPubMedGoogle Scholar
  27. 27.
    Christensen ER, Chen CY. A general noninteractive multiple toxicity model including probit, logit, and weibull transformations. Biometrics. 1985;41:711–25.CrossRefPubMedGoogle Scholar
  28. 28.
    Gessner PK. A straightforward method for the study of drug interactions: an isobolographic analysis primer. J Am Coll Toxicol. 1988;7(7):987–1012.Google Scholar
  29. 29.
    Fedeli L, Meneghini L, Sangiovanni M, Scrollini F, Gori E. Quantitative evaluation of joint drug action. In: de Baker SB, Neuhaus GA, editors. Toxicological problems of drug combinations. Amsterdam: Excerpta Medica; 1972. pp. 231–245.Google Scholar
  30. 30.
    Goldin A, Mantel N. The employment of combinations of drugs in the chemotherapy of neoplasia: a review. Cancer Res. 1957;17(7):635–54.PubMedGoogle Scholar
  31. 31.
    Le Blanc AE. Drug interactions Some first principles. In: Xintaras C, Johnson BL, deGroot C, editors. Behavioral toxicology. US Government. Department of Health, Education and Welfare; 1974.Google Scholar
  32. 32.
    Loewe S. Die Mischarznei Versuch einer allgemeinen Pharmakologie der Arzneikombinationen. Klin Wochenschr. 1927;6(23):1077–85.CrossRefGoogle Scholar
  33. 33.
    Plackett RS, Hewlett PS. Quantal responses to mixtures of poisons. J R Statist Soc. 1952;B14:141–63.Google Scholar
  34. 34.
    Loewe S. Randbemerkungen zur quantitativen Pharmakologie der Kombinationen. Drug Res. 1959;9:449–56.Google Scholar
  35. 35.
    Putnam AR, Penner D. Pesticides interactions in higher plants. Res Rev. 1974;50:73–110.Google Scholar
  36. 36.
    Chou TC, Talalay P. Analysis of combined drug effects: a new look to a very old problem. Trends Pharmacol Sci. 1983;11:450–4.CrossRefGoogle Scholar
  37. 37.
    Calamari D, Vighi M. A proposal to define quality objectives for aquatic life for mixtures of chemical substances. Chemosphere. 1992;25:531–42.CrossRefGoogle Scholar
  38. 38.
    Altenburger R, Backhaus T, Boedeker W, Faust M, Scholze M, Grimme LH. Predictability of the toxicity of multiple chemical mixtures to Vibrio fischeri: mixtures composed of similarly acting compounds. Environ Toxicol Chem. 2000;19:2341–7.Google Scholar
  39. 39.
    Backhaus T, Altenburger R, Boedeker E, Faust M, Scholze M, Grimme LH. Predictability of the toxicity of a multiple mixture of dissimilarly acting chemicals to Vibrio fischeri. Environ Toxicol Chem. 2000;19:2348–56.Google Scholar
  40. 40.
    Berenbaum MC. Synergy, additivsm and antagonism in immunosuppression. Clin Exp Immunol. 1977;28:1–18.PubMedGoogle Scholar
  41. 41.
    Wahrendorf J, Brown CC. Bootstrapping a basic inequality in the analysis of joint action of two drugs. Biometrics. 1980;36:653–7.CrossRefPubMedGoogle Scholar
  42. 42.
    Scholze M, Boedeker W, Faust M, Backhaus T, Altenburger R, Grimme LH. A general best-fit method for concentration-response curves and the estimation of low-effect concentrations. Environ Toxicol Chem. 2001;20:448–57.PubMedGoogle Scholar
  43. 43.
    Drescher K, Boedeker W. Assessment of the combined effect of substances: the relationship between concentration addition and independent action. Biometrics. 1995;51:716–30.CrossRefGoogle Scholar
  44. 44.
    Boedeker W, Drescher K, Altenburger R, Faust M, Grimme LH. Combined effects of toxicants: the need and soundness of assessment approaches in ecotoxicology. Sci Total Environ. 1993;134 Suppl 2:931–938.Google Scholar
  45. 45.
    Junghans M, Backhaus T, Faust M, Scholze M, Grimme LH. Application and validation of approaches for the predictive hazard assessment of realistic pesticide mixtures. Aqua Toxicol. 2006;76:93–110.CrossRefGoogle Scholar
  46. 46.
    Rothman KJ. Synergy and antagonism in cause-effect relationships. Amer J Epidemiol. 1974;99:385–8.Google Scholar
  47. 47.
    Rothman KJ. The estimation of synergy or antagonism. Amer J Epidemiol. 1976;103:506–11.Google Scholar
  48. 48.
    Walter SD, Holford TR. Additive, multiplicative, and other models for disease risks. Am J Epidemiol. 1978;108:341–6.PubMedGoogle Scholar
  49. 49.
    Miettinen OS. Causal and preventive interdependence. Elemetary principles. Scand J Work Environ Health. 1982;8:159–68.PubMedGoogle Scholar
  50. 50.
    Rothman KJ, Greenland S, Walker AM. Concepts of interaction. Am J Epidemiol. 1980;112:467–70.PubMedGoogle Scholar
  51. 51.
    Rothman KJ, Greenland S, Lash TL. Modern epidemiology. 3rd ed. Philadelphia: Kluwer; 2008.Google Scholar
  52. 52.
    VanderWeele TJ. Sufficient cause interactions and statistical interactions. Epidemiology. 2009;20(1):6–13.CrossRefPubMedGoogle Scholar
  53. 53.
    Greenland S, Poole C. Invariants and noninvariants in the concept of interdependent effects. Scand J Work Environ Health. 1988;14:125–9.PubMedGoogle Scholar
  54. 54.
    Kupper LL, Hogan MD. Interaction in epidemiologic studies. Am J Epidemiol. 1978;108:447–53.PubMedGoogle Scholar
  55. 55.
    Kodell RL, Gaylor DW. On the additive and multiplicative models of relative risk. Biom J. 1989;31:359–70.CrossRefGoogle Scholar
  56. 56.
    Kortenkamp A, Faust M, Scholze M, Backhaus T. Low-level exposure to multiple chemicals: reasons fur human health concerns? Environ Health Perspect. 2007;115(Suppl 1):106–14.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  1. 1.Federal Association of Company Health Insurance Funds (BKK Bundesverband), Initiative Work and HealthEssenGermany
  2. 2.Department of Plant and Environmental SciencesUniversity of GothenburgGothenburgSweden

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