The High Production Volume Chemical Challenge Program provides an opportunity to re-examine the usefulness and informational value of tests currently used to obtain preliminary hazard identification data. With a view to assessing the mechanistic information provided by the rodent LD50 test and to ascertain the possibility of replacing it with other “more acceptable” assays, we used a recently developed approach to determine the relationship of the LD50 assay to other toxicological protocols. Our analyses indicate that, of the assays examined, the LD50 was significantly related to toxicity in cultured cells and to binding at the Ah receptor.
LibowitzL.A. (1999). Letter from CAAT. ATLA27, 225–226.
3.
StokstadtE. (1999). Toxicity testing: the many arts of persuasion. Science, New York286, 1070.
4.
PollackN., CunninghamA.R., KlopmanG., & RosenkranzH.S. (1999). A new approach for evaluating mechanistic relatedness among toxicological phenomena. SAR and QSAR in Environmental Research10, 533–543.
5.
National Academy of Sciences (1984). Toxicity Testing: Strategies to Determine Needs and Priorities, 382 pp. Washington, DC, USA: National Academy Press.
6.
KlopmanG., & RosenkranzH.S. (1994). Prediction of carcinogenicity/mutagenicity using MULTICASE. Mutation Research305, 33–46.
7.
KlopmanG., & RosenkranzH.S. (1995). Toxicity estimation by chemical substructure analysis: the Tox II program. Toxicology Letters79, 145–155.
8.
ChankongV., HaimesY.Y., RosenkranzH.S., & Pet-EdwardsJ. (1985). The Carcinogenicity Prediction and Battery Selection (CPBS) method: a Bayesian approach. Mutation Research153, 135–166.
9.
ZhangY.P., SussmanN., MacinaO.T., RosenkranzH.S., & KlopmanG. (1996). Prediction of the carcinogenicity of a second group of chemicals undergoing carcinogenicity testing. Environmental Health Perspectives104, Suppl. 5, 1045–1050.
10.
MacinaO.T., ZhangY.P., & RosenkranzH.S. (1998). Improved predictivity of chemical carcinogens: the use of a battery of SAR models. In Carcinogenicity: Testing, Predicting and Interpreting Chemical Effects (ed. KitchinK.T.), pp. 227–250. New York, USA: Marcel-Dekker.
11.
RosenkranzH.S., CunninghamA.R., ZhangY.P., ClaycampH.G., MacinaO.T., SussmanN.B., GrantS.G., & KlopmanG. (1999). Development, characterization and application of predictive toxicology models. SAR and QSAR in Environmental Research10, 277–298.
12.
RannugU., SjogrenM., RannugA., GillnerM., ToftgardR., GustafssonJ-A., RosenkranzH., & KlopmanG. (1991). Use of artificial intelligence in structure-affinity correlations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) receptor ligands. Carcinogenesis12, 2007–2016.
13.
LiuM., SussmanN., KlopmanG., & RosenkranzH.S. (1996). Estimation of the optimal database size for structure-activity analyses: the Salmonella mutagenicity database. Mutation Research358, 63–72.
Mersch-SundermannV., SchneiderU., KlopmanG., & RosenkranzH.S. (1994). SOS-Induction in E. coli and Salmonella mutagenicity: a comparison using 330 compounds. Mutagenesis9, 205–224.
16.
Mersch-SundermannV., KlopmanG., & RosenkranzH.S. (1996). Chemical structure and genotoxicity: studies of the SOS chromotest. Mutation Research340, 81–91.
17.
AshbyJ., & TennantR.W. (1991). Definitive relationships among chemical structure, carcinogenicity and mutagenicity for 301 chemicals tested by the US NTP. Mutation Research257, 229–306.
18.
GoldL.S., SawyerC.B., MagawR., BackmanG.M., de VecianaM., LevinsonR., HooperN.K., HavenderW.R., BernsteinL., PetoR., PikeM.C., & AmesB.N. (1984). A carcinogenic potency database of the standardized results of animal bioassays. Environmental Health Perspectives58, 9–319.
19.
GoldL.S., de VecianaM., BackmanG.M., MagawR., LopiperoP., SmithM., BlumenthalM., LevinsonR., BernsteinL., & AmesB.N. (1986). Chronological supplement to the Carcinogenic Potency Database: standardized results of animal bioassays published through December 1982. Environmental Health Perspectives67, 161–200.
20.
GoldL.S., SloneT.H., BackmanG.M., MagawR., Da CostaM., LopiperoP., BlumenthalM., & AmesB.N. (1987). Second chronological supplement to the carcinogenic potency database: standardized results of animal bioassays published through December 1984 and by the National Toxicology Program through May 1986. Environmental Health Perspectives74, 237–329.
21.
GoldL.S., SloneT.H., BackmanG.M., EisenbergS., Da CostaM., WongM., ManleyN.B., RohrbachL., & AmesB.N. (1990). Third chronological supplement to the Carcinogenic Potency Database: standardized results of animal bioassays published through December 1986 and by the National Toxicology Program through June 1987. Environmental Health Perspectives84, 215–286.
22.
GoldL.S., ManleyN.B., SloneT.H., GarfinkelG.B., RohrbachL., & AmesB.N. (1993). The fifth plot of the Carcinogenic Potency Database: results of animal bioassays published in the general literature through 1988 and by the National Toxicology Program through 1989. Environmental Health Perspectives100, 65–135.
23.
GómezJ., MacinaO.T., MattisonD.R., ZhangY.P., KlopmanG., & RosenkranzH.S. (1999). Structural determinants of developmental toxicity in hamsters. Teratology60, 190–205.
24.
ZhangY.P., van PraaghA., KlopmanG., & RosenkranzH.S. (1994). Structural basis of the induction of unscheduled DNA synthesis in rat hepatocytes. Mutagenesis9, 141–149.
25.
YangW-L., KlopmanG., & RosenkranzH.S. (1992). Structural basis of the in vivo induction of micronuclei. Mutation Research272, 111–124.
26.
NendzaM., & RussomC.L. (1991). QSAR modelling of the ERL-D fathead minnow acute toxicity database. Xenobiotica21, 147–170.
27.
RosenkranzH.S., MatthewsE.J., & KlopmanG. (1992). Relationship between cellular toxicity, the maximum tolerated dose, lipophilicity and electrophilicity. ATLA20, 549–562.
28.
ZhuX., KlopmanG., & RosenkranzH.S. (1999). Evaluating the cytotoxicity of 181 chemicals to HeLa cells using SAR expert system. The Toxicologist48, 373.
29.
EkwallB. (1980). Toxicity to HeLa cells of 205 drugs as determined by the metabolic inhibition test supplemented with microscopy. Toxicology17, 273–295.
30.
HoelD.G., HasemanJ.K., HoganM.D., HuffJ., & McConnellE.E. (1988). The impact of toxicity on carcinogenicity studies: implications for risk assessment. Carcinogenicity9, 2045–2052.
31.
ZeiseL., CrouchE.A.C., & WilsonR. (1986). A possible relationship between toxicity and carcinogenicity. Journal of the American College of Toxicology5, 137–151.
32.
FreedmanD.A., GoldL.S., & StoneT.H. (1993). How tautological are interspecies correlations of carcinogenic potency?Risk Analysis13, 265–275.
33.
AmesB.N., & GoldL.S. (1990). Chemical carcinogenesis: too many rodent carcinogens. Proceedings of the National Academy of Sciences, USA7, 7772–7776.
34.
CohenS.M., & EllweinL.B. (1990). Cell proliferation in carcinogenesis. Science, New York249, 1007–1011.
35.
CohenS.M., & EllweinL.B. (1991). Genetic errors, cell proliferation and carcinogenesis. Cancer Research51, 6493–6505.
36.
Preston-MartinS., PikeM.C., RossR.K., JonesP.A., & HendersonB.E. (1990). Increased cell division as a cause of human cancer. Cancer Research50, 7415–7421.
37.
CarlsonR.M. (1990). Assessment of the propensity for covalent binding of electrophiles to biological substrates. Environmental Health Perspectives87, 227–232.
38.
EkwallB. (1999). Overview of the final MEIC results. II. The in vitro–in vivo evaluation, including the selection of a practical battery of cell tests for prediction of acute lethal blood concentrations in humans. Toxicology in Vitro13, 665–673.
39.
EkwallB., ClemedsonC., EkwallB., RingP., & RomertL. (1999). EDIT: a new international multicentre programme to develop and evaluate batteries of in vitro tests for acute and chronic systemic toxicity. ATLA27, 339–349.
40.
BlaauboerB.J., BarrattM.D., & HoustonJ.B. (1999). The integrated use of alternative methods in toxicological risk evaluation. ATLA27, 229–237.
41.
SchardeinJ.L. (1993). Chemically Induced Birth Defects, 902 pp. New York, USA: Marcel Dekker.
42.
SwenbergJ.A., ShortB., BorghoffS., StrasserJ., & CharbonneauM. (1989). The comparative pathobiology of an α2μ-globulin nephropathy. Toxicology and Applied Pharmacology97, 35–46.
