The Role of Mechanistic Data in Dose-Response Modeling

  • Thomas B. Starr
Part of the Basic Life Sciences book series

Abstract

A critical issue in carcinogenic dose-response modeling involves the functional form of the relationship between the two distinct measures of exposure denoted by the terms administered dose and delivered dose. Administered dose refers to the external measures of exposure that are directly controlled in laboratory studies of toxicity. For inhalation studies, it typically denotes the concentration of a test chemical in the inhalation chamber air. In contrast, delivered dose refers to internal measures of exposure, such as the quantity or concentration of the biologically active form of a test chemical that is present in specific target tissue components. It is this latter measure, the delivered dose, that is presumed to be the direct causative variable in mechanistic descriptions of the carcinogenic process at the cellular and molecular levels.

Keywords

Formaldehyde Toxicity Depression Aldehyde Adduct 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Bolt, H. M., Kappus, H., Kaufmann, R., Appel, K. E., Buchter, A., and Bolt, W., 1975, Metabolism of [14C]-vinyl chloride in vitro and in vivo, Inserm., 52:151.Google Scholar
  2. Casanova-Schmitz, M., and Heck, H. d’A., 1983, Effects of formaldehyde exposure on the extractability of DNA from proteins in the rat nasal mucosa, Toxicol. Appl. Pharmacol., 70:121.PubMedCrossRefGoogle Scholar
  3. Casanova-Schmitz, M., Starr, T. B., and Heck, H. d’A., 1984, Differentiation between metabolic incorporation and covalent binding in the labeling of macromolecules in the rat nasal mucosa and bone marrow by inhaled [C]- and [H]formaldehyde, Toxicol. Appl. Pharmacol., 76:26.PubMedCrossRefGoogle Scholar
  4. Gehring, P. J., Watanabe, P. G., and Park, C. N., 1978, Resolution of dose-response toxicity data for chemicals requiring metabolic activation. Example: vinyl chloride, Toxicol. Appl. Pharmacol., 44:581.PubMedCrossRefGoogle Scholar
  5. Hoel, D. G., Kaplan, N. L., and Anderson, M. W., 1983, Implication of nonlinear kinetics on risk estimation in carcinogenesis, Science, 219:1032.PubMedCrossRefGoogle Scholar
  6. Kerns, W. D., Pavkov, K. L., Donofrio, D. J., and Swenberg, J. A., 1983, Carcinogenicity of formaldehyde in rats and mice after long-term inhalation exposure, Cancer Res., 43:4382.PubMedGoogle Scholar
  7. Maltoni, C., and Lefemine, G., 1975, Carcinogenicity assays of vinyl chloride: Current results, Ann. N.Y. Acad. Sci., 246:195.PubMedCrossRefGoogle Scholar
  8. Morgan, K. T., Patterson, D. L., and Gross, E. A., 1983, Formaldehyde and the nasal mucociliary apparatus, in : “Formaldehyde: Toxicology, Epidemiology, Mechanisms,” pp. 193–209, J. J. Clary, J. E. Gibson, and R. S. Waritz, eds., Marcel Dekker, New York.Google Scholar
  9. Reitz, R. H., Quast, J. F., Schumann, A. M., Watanabe, P. G., and Gehring, P. J., 1980, Non-linear pharmacokinetic parameters need to be considered in high dose/low dose extrapolation, in: “Quantitative Aspects of Risk Assessment in Chemical Carcinogenesis,” Arch. Toxicol., Suppl. 3:79.CrossRefGoogle Scholar
  10. Starr, T. B., and Buck, R. D., 1984, The importance of delivered dose in estimating low-dose cancer risk from inhalation exposure to formaldehyde, Fundam. Appl. Toxicol., 4:740.PubMedCrossRefGoogle Scholar
  11. Swenberg, J. A., Barrow, C. S., Boreiko, C. J., Heck, H. d’A., Levine, R. J., Morgan, K. T., and Starr, T. B., 1983a, Nonlinear biological responses to formaldehyde and their implications for carcinogenic risk assessment, Carcinogenesis, 4:945.PubMedCrossRefGoogle Scholar
  12. Swenberg, J. A., Gross, E. A., Randall, H. W., and Barrow, C. S., 1983b, The effect of formaldehyde exposure on cytotoxicity and cell proliferation, in: “Formaldehyde: Toxicology, Epidemiology, Mechanisms,” pp. 225–236, J. J. Clary, J. E. Gibson, and R. S. Waritz, eds., Marcel Dekker, New York.Google Scholar
  13. Van Ryzin, J., and Rai, K., 1980, The use of quantal response data to make predictions, in: “The Scientific Basis of Toxicity Assessment,” pp. 273–290, H. R. Witschi, ed., Elsevier/North Holland, New York.Google Scholar
  14. Watanabe, P. G., Hefner Jr., R. E., and Gehring, P. J., 1976, Fate of [14C]-vinyl chloride following inhalation exposure in rats, Toxicol. Appl. Pharmacol., 37:49.PubMedCrossRefGoogle Scholar
  15. Crump, K.S., Guess, H.A., and Deal, K.L., 1977, Confidence intervals and test of hypotheses concerning dose/response relations inferred from animal carcinogenicity data, Biometrics, 33:437.PubMedCrossRefGoogle Scholar
  16. Peto, R., 1978a, Control of industrially induced cancers, Env. Health Persp., 22:153.CrossRefGoogle Scholar
  17. Peto, R., 1978b, Carcinogenic effects of chronic exposure to low levels of toxic substances, Env. Health Persp., 22:155.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1985

Authors and Affiliations

  • Thomas B. Starr
    • 1
  1. 1.Department of EpidemiologyChemical Industry Institute of ToxicologyResearch Triangle ParkUSA

Personalised recommendations