Predictive Value of In Vitro Systems for Neurotoxicity Risk Assessment

  • Marion Ehrich
  • David C. Dorman
Part of the Methods in Pharmacology and Toxicology book series (MIPT)


Risk assessment has been broadly defined as the characterization of the adverse health effects of human exposures to environmental hazards and can be divided into four major steps: hazard identification, dose-response assessment, exposure assessment, and risk characterization (1). Hazard identification is defined as determining whether human exposure to an agent can cause an increased incidence of an adverse health effect (e.g., neurotoxicity). Dose-response assessment is the process of characterizing the relationship between the administered or effective dose of an agent and the incidence of an adverse health effect in exposed populations, estimating the incidence of the effect as a function of human exposure to the agent. A dose-response assessment should account for exposure intensity and duration, developmental age, and other factors that may modify the response (e.g., gender, diet). Exposure assessment is the process of measuring or estimating the intensity, frequency, and duration of human exposure to an agent found in the environment or an agent that may be released into the environment. Risk characterization integrates these preceding steps by estimating the incidence of a health effect under various conditions of human exposure.


Human Exposure Adverse Health Effect Organophosphorus Compound Risk Characterization Risk Assessment Process 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    National Research Council (1983). Risk Assessment in the Federal Government: Managing the Process, National Academy Press, Washington, DC.Google Scholar
  2. 2.
    Costa, L. G. (1998a) Neurotoxicity testing: a discussion of in vitro alternatives. Environ. Health Perspect. 106S, 505–510.CrossRefGoogle Scholar
  3. 3.
    Harry, G. J., Billingsley, M., Bruinink, A., et al. (1998) In vitro techniques for the assessment of neurotoxicity. Environ. Health Perspect. 106S, 131–158.CrossRefGoogle Scholar
  4. 4.
    National Research Council Committee on Neurotoxicology and Models for Assessing Risk (1992) Environmental Neurotoxicology, National Academy Press, Washington, DC.Google Scholar
  5. 5.
    US Environmental Protection Agency (1991) Pesticide Assessment Guidelines, Subdivision E. Hazard Evaluation: Human and Domestic Animals (Addendum 10: Neurotoxicity, series 81, 82, and 83), Office of Prevention, Pesticides and Toxic Substances, Washington, DC.Google Scholar
  6. 6.
    US Food and Drug Administration Center for Food Safety and Applied Nutrition. (1993) Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food, US Food and Drug Administration, Washington, D.C.Google Scholar
  7. 7.
    Ehrich, M. and Veronesi, B. (1999) In vitro neurotoxicology, in Neurotoxicology (Tilson, H. A. and Harry, G. J., eds.), Taylor & Francis, Philadelphia, pp. 37–51.Google Scholar
  8. 8.
    Flint, O. P. (1999) An introduction to the practical applications of new in vitro tests, in Neurotoxicology in Vitro (Pentreath, V. W., ed.), Taylor & Francis, Philadelphia, pp. 3–16.Google Scholar
  9. 9.
    Dorman, D. C. (2000). An integrative approach to neurotoxicology. Toxicol. Pathol. 28, 37–42.PubMedCrossRefGoogle Scholar
  10. 10.
    Campbell, I. C., Fletcher, L., Grant, P. A. A., and Abdulla, E. M. (1996) Validation of in vitro tests in neurotoxicology. ATLA 24, 339–347.Google Scholar
  11. 11.
    Purchase, I. F. H. (1996) In vitro toxicology methods in risk assessment. ATLA 24, 325–331.Google Scholar
  12. 12.
    Halks-Miller, M., Fedor, V., and Tyson, C. A. (1991) Overview of approaches to in vitro neurotoxicity testing. J. Am. Coll. Toxicol. 10, 727–736.Google Scholar
  13. 13.
    Tiffany-Castiglioni, E., Ehrich, M., Dees, L., et al. (1999) Bridging the gap between in vitro and in vivo models for neurotoxicology. Toxicol. Sci. 51, 178–183.PubMedCrossRefGoogle Scholar
  14. 14.
    Veronesi, B., Ehrich, M., Blusztain, J. K., Oortgiesen, M., and Durham, H. (1997) Cell culture models of interspecies selectivity to organophosphorus insecticides. Neurotoxicology 18, 283–298.PubMedGoogle Scholar
  15. 15.
    Atterwill, C. K., Bruinink, A., Drejer, J., et al. (1994) In vitro neurotoxicity tests, the report and recommendations of ECVAM workshop 3. ATLA 22, 350–362.Google Scholar
  16. 16.
    Balls, M. and Walum, E. (1999) Towards the acceptance of in vitro neurotoxicity tests, in Neurotoxicology in Vitro (Pentreath, V. W., ed.), Taylor & Francis, Philadelphia, pp. 269–283.Google Scholar
  17. 17.
    Slikker, W. Jr., Crump, K. S., Anderson, M. E., and Bellinger, D. (1996) Biologically based, quantitative risk assessment of neurotoxicants. Fundam. Appl. Toxicol. 229, 18–30.CrossRefGoogle Scholar
  18. 18.
    Costa, L. G. (1998) Biochemical and molecular neurotoxicology: relevance to biomarker development, neurotoxicity testing and risk assessment. Toxicol. Lett. 102–103, 417–421.PubMedCrossRefGoogle Scholar
  19. 19.
    Forsby, A., Pilli, F., Bianchi, V., and Walum, E. (1995) Determination of critical cellular neurotoxic concentrations in human neuroblastoma (SH-SY5Y) cell cultures. ATLA 23, 800–811.Google Scholar
  20. 20.
    Clemedson, C., McFarlane-Abdulla, E., Andersson, M., et al. (1996) MEIC evaluation of acute systemic toxicity. Part II. In vitro results from 68 toxicity assays used to test the first 30 reference chemicals and a comparative cytotoxicity analysis. ATLA 24, 273–311.Google Scholar
  21. 21.
    Walum, E., Forsby, A., Clemedson, C., and Ekwall, B. (1996) Dynamic qualities of validation and the evoluation of new in vitro toxicological tests. ATLA 24, 333–338.Google Scholar
  22. 22.
    Ehrich, M. (1998) Human cells as in vitro alternatives for toxicological research and testing: neurotoxicity studies. Comments Toxicol. 6, 189–198.Google Scholar
  23. 23.
    Dorman, D. C., Struve, M. F., and Morgan, K. T. (1993) In vitro neurotoxicity research at CIIT. CIIT Activities 13(11–12), 1–8.Google Scholar
  24. 24.
    Ray, D. E. (1999) Toxic cell damage, in Neurotoxicology in Vitro (Pentreath, V. W., ed.), Taylor & Francis, Philadelphia, pp. 77–103.Google Scholar
  25. 25.
    Ehrich, M., Correll, L., and Veronesi, B. (1997) Acetylcholinesterase and neuropathy target esterase inhibitions in neuroblastoma cells to distinguish organophosphorus compounds causing acute and delayed neurotoxicity. Fundam. Appl. Toxicol. 38, 55–63.PubMedCrossRefGoogle Scholar
  26. 26.
    Veronesi, B. and Ehrich, M. (1993). Differential cytotoxic sensitivity in mouse and human cell lines exposed to organophosphate insecticides. Toxicol. Appl. Pharmacol. 120, 240–246.PubMedCrossRefGoogle Scholar
  27. 27.
    Ehrich, M. and Correll, L. (1998). Inhibition of carboxylesterases in SH-SY5Y human and NB41A3 mouse neuroblastoma cells by organophosphorus esters. J. Toxicol. Environ. Health 53A, 385–399.Google Scholar
  28. 28.
    Carlson, K., Jortner, B. S., and Ehrich, M. (2000). Organophosphorus compound-induced apoptosis in SH-SY5Y human neuroblastoma cells. Toxicol. Appl. Pharmacol. 168, 102–113.PubMedCrossRefGoogle Scholar
  29. 29.
    Barber, D., Correll, L., and Ehrich, M. (1999) Comparison of two in vitro activation systems for protoxicant organophosphorous esterase inhibitors. Toxicol. Sci. 47, 6–22.CrossRefGoogle Scholar
  30. 30.
    Golub, M. S., Han, B., and Keen, C. L. (1999). Aluminum uptake and effects on transferrin mediated iron uptake in primary cultures of rat neurons, astrocytes and oligodendrocytes. Neurotoxicology 20, 961–970PubMedGoogle Scholar
  31. 31.
    Roberts, R., Sandra, A., Siek, G. C., Lucas, J. J., and Fine, R. E. (1992). Studies of the mechanism of iron transport across the blood-brain barrier. Ann. Neurol. 32 S, 43–50.CrossRefGoogle Scholar
  32. 32.
    Aschner, M. and Clarkson, T. W. (1989). Methyl mercury uptake across bovine brain capillary endothelial cells in vitro: the role of amino acids. Pharmacol. Toxicol. 64, 293–297.PubMedCrossRefGoogle Scholar
  33. 33.
    Hu, H. L., Bennett, N., Lamb, J. H., Ghersi-Egea, J.F., Schlosshauer, B., and Ray, D. E. (1997). Capacity of rat brain to metabolize m-dinitrobenzene: an in vitro study. Neurotoxicology 18, 363–370.PubMedGoogle Scholar
  34. 34.
    Song, X. and Ehrich, M. (1998). Uptake and metabolism of MPTP and MPP+ in SH-SY5Y human neuroblastoma cells. In Vitro Mol. Toxicol. 11, 3–14.Google Scholar
  35. 35.
    Corsini, G. U., Pintus, S., Bocchetta, A., Piccardi, M. P., and Del Zompo, M. (1986). A reactive metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine is formed in rat brain in vitro by type B monoamine oxidase. J. Pharmacol. Exp. Ther. 238, 648–652.PubMedGoogle Scholar
  36. 36.
    Mortenson, S. R., Brimijoin, S., Hooper, M. J., and Padilla, S. (1998) Comparison of the in vitro sensitivity of rat acetylcholinesterase to chlorpyrifosoxon: What do tissue IC50 values represent? Toxicol. Appl. Pharmacol. 148, 46–59.CrossRefGoogle Scholar
  37. 37.
    Clothier, R. H., Hulme, L. M., Smith, M., and Balls, M. (1987) Comparison of the in vitro cytotoxicities and acute in vivo toxicities of 59 chemicals. Mol. Toxicol. 1, 571–577PubMedGoogle Scholar

Copyright information

© Humana Press Inc., Totowa, NJ 2004

Authors and Affiliations

  • Marion Ehrich
    • 1
  • David C. Dorman
    • 2
  1. 1.Virginia-Maryland Regional College of Veterinary MedicineBlacksburg
  2. 2.Division of Biological SciencesCIIT Centers for Health ResearchResearch Triangle Park

Personalised recommendations