Cell Biology and Toxicology

, Volume 8, Issue 2, pp 157–170 | Cite as

Comparison of in vivo acute lethal potency and in vitro cytotoxicity of 48 chemicals

  • R. Shrivastava
  • C. Delomenie
  • A. Chevalier
  • G. John
  • B. Ekwall
  • E. Walum
  • R. Massingham
Article

Abstract

The cytotoxicity of 48 compounds included in the MEIC (Multicenter Evaluation of In Vitro Cytotoxicity) list was determined in cultures of rat hepatocytes, McCoy, and MDBK cells. The average minimum concentration of each compound inducing cytotoxicity was measured in each cell type. The cytotoxicity values were then compared with published oral LDS p values for rats and mice. The logarithmic transformation of in vivo toxic doses and the corresponding in vitro cytotoxic concentrations showed a statistically significant correlation between the in vitro and in vivo values. The results show that an accurate in vivo LDS p dose could be predicted from in vitro data for at least 75% of the selected compounds. It is hoped that this finding will not only stimulate others to pursue in vitro technique but will eventually lead to elimination of the in vivo LD50 test.

Abbreviations

CT50

50% cytotoxic concentration

CT100

100% cytotoxic concentration

DMSO

dimethyl sulfoxide

LD50

50% lethal dose

LDH

Lactate dehydrogenase

MEIC

Multicenter Evaluation of In Vitro Cytotoxicity

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. ADLER, E., BENJAMIN, S.B., and ZIMMERMAN, H.J. (1986). “Cholestatic hepatic injury related to Warfarin exposure.” Arch. Intern. Med. 46: 1837–1839.Google Scholar
  2. ALDHOUS, P. (1991). “Tide turns against LD50.” Nature 352:489.Google Scholar
  3. BODYAGIN, D.A., SIRKIN, A.B., LUTINOSOV., Y.V., and ZAITSEVA, L.A. (1989). “The effect on human and animal organisms of herbicide derivatives of chlorophenoxy acetic acid.” Farmakol. Toksikol. 32: 747–751.Google Scholar
  4. BONDESSON, I., EKWALL, B., HELLBERG, S., ROMBERT, L., STENBERG, K., and WALUM, E. (1989). “MEIC—A new international multicenter project to evaluate the relevance to human toxicity of in vitro cytotoxicity tests.” Cell. Biol. and Toxicol. 5: 331–247.Google Scholar
  5. 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: 571–577.Google Scholar
  6. EKWALL, B. (1980). “Preliminary studies on the validity of in vitro measurement of drug toxicity using HeLa cells. II. Drug toxicity in the MIT-24 system compared with mouse and human lethal dosage of 52 drugs.” Toxicol. Letters. 5: 309–317.Google Scholar
  7. EKWALL, B. and JOHANSSON, A. (1980). “Preliminary studies on the validity of in vitro measurement of drug toxicity using HeLa cells. I. Comparative in vitro toxicity of 27 drugs.” Toxicol. Letters. 5:299–307.Google Scholar
  8. EKWALL, B. (1981). “Preliminary studies on the validity of in vitro measurement of drug toxicity using HeLa cells. IV. Therapeutic effects and side effects of 50 drugs related to the HeLa toxicity of the therapeutic concentrations.” Toxicol. Letters. 7: 359–366.Google Scholar
  9. EKWALL, B. (1983). “Correlation between cytotoxicity in vitro and LD50-values.” Pharmacologica Toxicologica 52: 80–99.Google Scholar
  10. EKWALL, B., GOMEZ-LECHON, M.J., HELLBERG, S., BONDESSON, I., CASTELL, J.V., JOVER, R., HOGBERG, J., PONSODA, X., ROMER, L., STENBERG, K., and WALUM, E. (1990). “Preliminary results from the scandanavian multicentre evaluation of in vitro cytotoxicity (MEIC).” Toxicol. in vitro 4: 688–691.Google Scholar
  11. FRY, J.R., GARLE, M.J., HAMMOND, H.H., and HATFIELD, A. (1990). “Correlation of acute lethal potency with in vitro cytotoxicity.” Toxicol. in vitro 4: 175–178.Google Scholar
  12. GUILLOUZO, C.G. and GUILLOUZO, A. (1983). Modulation of functional activities in cultured rat hepatocytes.” Mol. Cell. Biochem. 53: 35–56.Google Scholar
  13. HALLE, W., GORES, E., and BAEGER, I. (1987). “Besitzt die vorhersage der LD50 mit hilfe der zellkultur allgemeingultigkeit? Pharmazie. 42: 848–850.Google Scholar
  14. HEUVEL, M.J., CLARK, D.G., FIELDER, R.J., KOUNDAKJIAN, P.P., OLIVER, G.J.A., PELLING, D., TOMLINSON, N.J., and WALKER, A.P. (1990). “The international validation of a fixed dose procedure as an alternative to the classical LD50 test.” Fd. Chem. Toxicol. 28: 469–482.Google Scholar
  15. MALANSKY, C.J. and WILLIAMS, G.M. (1982). “Primary cultures and the levels of cytochrome P450 in hepatocytes from mouse, rat, hamster and rabbit liver.” In vitro 18: 683–693.Google Scholar
  16. MEHLMAN, M.A., PFITZER, E.A., and SCALA, R.A. (1989). “A report on methods to reduce, refine, and replace animal testing in industrial toxicology laboratories.” Cell. Biol. and Toxicol. 5: 349–358.Google Scholar
  17. MEYER, H., BAUMANN, H.R., and LEMENBERGER, P. (1988). Meyler's side effects of drugs. Elsevier, Amsterdam.Google Scholar
  18. MOLDEUS, P., HOGBERG, J., and ORRENIUS, S. (1978). “Isolation and use of liver cells.” Methods. Enzymol. 52: 60–71.Google Scholar
  19. NOORDWIJK, A.J.V. and NOORDWIJK, J.V. (1988). “An accurate method for estimating an approximate lethal dose with few animals, tested with a Monte Carlo procedure. ” Arch. Toxicol. 61: 333–343.Google Scholar
  20. ROWAN, A. (1983). “Shortcomings of LD50-values and acute toxicity testing in animals.” Acta. Pharmacol. Toxicol. 52 (Suppl. II): 52–63.Google Scholar
  21. SCHALM, S.W. and DE KNEGT, R.J. (1984). Hepatic encephalopathy. Putative toxins: Phenol. Elsevier, Amsterdam.Google Scholar
  22. SHRIVASTAVA, R., JOHN, G.W., RISPAT, G., CHEVALIER, A., and MASSINGHAM, R. (1991). “Can the in vivo maximum tolerated dose be predicted using in vitro techniques? A working hypothesis.“ ATLA 19: 393–402.Google Scholar
  23. STRICKER, B.H. (1987). Hepatic injury by drugs and environmental toxins in the Liver Annual. Elsevier, Amsterdam.Google Scholar
  24. THURMAN, R.G. and KAUFFMAN, F.C. (1980). “Factors regulating drug metabolism in intact hepatocytes.” Pharmacol. Rev. 31: 229–251.Google Scholar
  25. TREVAN, J.W. (1927). “The error of determination of toxicity.” Proc. R. Soc. (Lond.) Ser. B. 101: 483–514.Google Scholar
  26. ZBINDEN, G. (1990). “Alternatives to animal experimentation: developing in vitro methods and changing legislation.” Tips 11: 104–107.Google Scholar

Copyright information

© Princeton Scientific Publishing Co., Inc 1991

Authors and Affiliations

  • R. Shrivastava
    • 1
  • C. Delomenie
    • 1
  • A. Chevalier
    • 1
  • G. John
    • 1
  • B. Ekwall
    • 2
  • E. Walum
    • 3
  • R. Massingham
    • 1
  1. 1.RL-CERMRiomFrance
  2. 2.Department of ToxicologyUniversity of UppsalaSweden
  3. 3.Department of Neurochemistry and NeurotoxicologyUniversity of StockholmSweden
  4. 4.RL-CERMRiom CedexFrance

Personalised recommendations