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

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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.

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References

  1. Calabrese EJ. Multiple chemical interaction. Chesia: Lewis Publishers; 1991.

    Google Scholar 

  2. Pöch G. Combined effects of drugs and toxic agents. Modern evaluation intheory and practice. Wien: Springer; 1993.

    Google Scholar 

  3. Chou TC. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev. 2006;58:621–81.

    Article  CAS  PubMed  Google Scholar 

  4. Berenbaum MC. The expected effect of a combination of agents: the general solution. J Theor Biol. 1985;114:413–31.

    Article  CAS  PubMed  Google Scholar 

  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. Faust M, Altenburger R, Boedeker W, Grimme LH. Algal toxicity of binary combinations of pesticide. Bull Environ Contam Toxicol. 1994;53:134–41.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  11. Altenburger R, Greco WR. Extrapolation concepts for dealing with multiple contamination in environmental risk assessment. Integr Environ Assess Manage. 2009;5:62–8.

    Article  CAS  Google Scholar 

  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. Kaufman JS. Interaction reaction. Epidemiology. 2009;20(2):159–60.

    Article  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  15. Greenland S. interactions in epidemiology: relevance, identification, and estimation. Epidemiology. 2009;20(1):14–7.

    Article  PubMed  Google Scholar 

  16. Unkelbach HD, Wolf T. Drug combinations—concepts and terminology. Arzneim Forsch. 1984;34 II(9):935–8.

    Google Scholar 

  17. Loewe S, Muischnek H. Über Kombinationswirkungen I. Mitteilung: Hilfsmittel der Fragestellung. Naunyn-Schmiedebergs Arch Exp Pathol u Pharmakol. 1926;114:313–26.

    Article  CAS  Google Scholar 

  18. Bliss CI. The toxicity of poisons applied jointly. Ann Appl Biol. 1939;26:585–615.

    Article  CAS  Google Scholar 

  19. Finney DJ. The analysis of toxicity tests on mixtures of poisons. Ann Apll Biol. 1942;29:82–94.

    Article  CAS  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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. Marking LL. Toxicity of chemical mixtures. In: Rand GM, Petrocelli SR, editors. Fundamentals of aquatic toxicology. Washington: Hemisphere Publishing Corporation; 1977.

    Google Scholar 

  23. Könemann H. Quantitative structure-activity relationships in fish toxicity studies Part 1: relationship for 50 industrial pollutants. Toxicology. 1980;19:209–21.

    Article  Google Scholar 

  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.

    CAS  Google Scholar 

  25. Morse PM. Some comments on the assessment of joint action in herbicide mixtures. Weed Sci. 1978;26(1):58–71.

    CAS  Google Scholar 

  26. Berenbaum MC. Criteria for Analysing Interactions between biologically active agents. Adv Cancer Res. 1981;35:269–335.

    Article  CAS  PubMed  Google Scholar 

  27. Christensen ER, Chen CY. A general noninteractive multiple toxicity model including probit, logit, and weibull transformations. Biometrics. 1985;41:711–25.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

  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.

    CAS  PubMed  Google Scholar 

  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.

  32. Loewe S. Die Mischarznei Versuch einer allgemeinen Pharmakologie der Arzneikombinationen. Klin Wochenschr. 1927;6(23):1077–85.

    Article  Google Scholar 

  33. Plackett RS, Hewlett PS. Quantal responses to mixtures of poisons. J R Statist Soc. 1952;B14:141–63.

    Google Scholar 

  34. Loewe S. Randbemerkungen zur quantitativen Pharmakologie der Kombinationen. Drug Res. 1959;9:449–56.

    CAS  Google Scholar 

  35. Putnam AR, Penner D. Pesticides interactions in higher plants. Res Rev. 1974;50:73–110.

    CAS  Google Scholar 

  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.

    Article  Google Scholar 

  37. Calamari D, Vighi M. A proposal to define quality objectives for aquatic life for mixtures of chemical substances. Chemosphere. 1992;25:531–42.

    Article  Google Scholar 

  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.

    CAS  Google Scholar 

  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.

    CAS  Google Scholar 

  40. Berenbaum MC. Synergy, additivsm and antagonism in immunosuppression. Clin Exp Immunol. 1977;28:1–18.

    CAS  PubMed  Google Scholar 

  41. Wahrendorf J, Brown CC. Bootstrapping a basic inequality in the analysis of joint action of two drugs. Biometrics. 1980;36:653–7.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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. 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.

    Article  CAS  Google Scholar 

  46. Rothman KJ. Synergy and antagonism in cause-effect relationships. Amer J Epidemiol. 1974;99:385–8.

    CAS  Google Scholar 

  47. Rothman KJ. The estimation of synergy or antagonism. Amer J Epidemiol. 1976;103:506–11.

    CAS  Google Scholar 

  48. Walter SD, Holford TR. Additive, multiplicative, and other models for disease risks. Am J Epidemiol. 1978;108:341–6.

    CAS  PubMed  Google Scholar 

  49. Miettinen OS. Causal and preventive interdependence. Elemetary principles. Scand J Work Environ Health. 1982;8:159–68.

    CAS  PubMed  Google Scholar 

  50. Rothman KJ, Greenland S, Walker AM. Concepts of interaction. Am J Epidemiol. 1980;112:467–70.

    CAS  PubMed  Google Scholar 

  51. Rothman KJ, Greenland S, Lash TL. Modern epidemiology. 3rd ed. Philadelphia: Kluwer; 2008.

    Google Scholar 

  52. VanderWeele TJ. Sufficient cause interactions and statistical interactions. Epidemiology. 2009;20(1):6–13.

    Article  PubMed  Google Scholar 

  53. Greenland S, Poole C. Invariants and noninvariants in the concept of interdependent effects. Scand J Work Environ Health. 1988;14:125–9.

    CAS  PubMed  Google Scholar 

  54. Kupper LL, Hogan MD. Interaction in epidemiologic studies. Am J Epidemiol. 1978;108:447–53.

    CAS  PubMed  Google Scholar 

  55. Kodell RL, Gaylor DW. On the additive and multiplicative models of relative risk. Biom J. 1989;31:359–70.

    Article  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Federal Association of Company Health Insurance Funds (BKK Bundesverband), Initiative Work and Health, Kronprinzenstraße 6, 45128, Essen, Germany

    Wolfgang Boedeker

  2. Department of Plant and Environmental Sciences, University of Gothenburg, Gothenburg, Sweden

    Thomas Backhaus

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  1. Wolfgang Boedeker
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  2. Thomas Backhaus
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Correspondence to Wolfgang Boedeker.

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Boedeker, W., Backhaus, T. The scientific assessment of combined effects of risk factors: different approaches in experimental biosciences and epidemiology. Eur J Epidemiol 25, 539–546 (2010). https://doi.org/10.1007/s10654-010-9464-2

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