NTP Technical Report on the Toxicity and Metabolism Studies of Chloral Hydrate (CAS No. 302-17-0) Administered by Gavage to F344/N Rats and B6C3F1Mice

NTP Technical Report on the Toxicity Studies Series

Volumn TOX-59, Issue , 1999, Pages 1-138

  Beland, Frederick A ^a   Fu, P P ^d   Allaben, W T ^d   Casciano, D A ^d   Dooley, K L ^d   Fullerton, N F ^d   Kadlubar, F F ^d   Littlefield, N A ^d   Ni, Y C ^d   Schmitt, T C ^d   Wong, T Y ^d   Young, J F ^d   Sheldon, W G ^b   Thurman, J D ^b   Witt, K L ^c   Morris, R W ^d   McGowan, K P ^d   Mauney, M A ^d   Mintz, N G ^d   Scott, J T ^d   Gunnels, S R ^d   MacRi Hanson, A M ^d   Rathman, E S ^d   Sharp, W D ^d   more..

^a NATIONAL CENTER FOR TOXICOLOGICAL RESEARCH   (United States)

^b Pathology Associates International

^c INTEGRATED LABORATORY SYSTEMS   (United States)

^d NONE

Author keywords

[No Author keywords available]

Indexed keywords

CHLORAL HYDRATE; DNA; HYPNOTIC SEDATIVE AGENT;

ANIMAL; ARTICLE; BODY WEIGHT; CHO CELL; DNA ADDUCT; DRUG EFFECT; FISCHER 344 RAT; HAMSTER; HUMAN; IN VITRO STUDY; LD 50; LIVER MICROSOME; MALE; METABOLISM; MOUSE; MOUSE STRAIN; MUTAGEN TESTING; ORGAN SIZE; RAT; STOMACH LAVAGE; TISSUE DISTRIBUTION; WATER POLLUTANT;

ANIMALS; BODY WEIGHT; CHLORAL HYDRATE; CHO CELLS; CRICETINAE; DNA; DNA ADDUCTS; GASTRIC LAVAGE; HUMANS; HYPNOTICS AND SEDATIVES; LETHAL DOSE 50; MALE; MICE; MICE, INBRED STRAINS; MICROSOMES, LIVER; MUTAGENICITY TESTS; ORGAN SIZE; RATS; RATS, INBRED F344; TISSUE DISTRIBUTION; WATER POLLUTANTS, CHEMICAL;

EID: 0033180665     PISSN: 23788984     EISSN: 23788992     Source Type: Book Series    
DOI: None     Document Type: Review

References (124)

1. Abbas, R.R., Seckel, C.S., Kidney, J.K., and Fisher, J.W. (1996). Pharmacokinetic analysis of chloral hydrate and its metabolism in B6C3F1 mice. Drug Metab. Dispos. 24, 1340-1346.
2. Adler, I.D., Kliesch, U., van Hummelen, P., and Kirsch-Volders, M. (1991). Mouse micronucleus tests with known and suspect spindle poisons: Results from two laboratories. Mutagenesis 6, 47-53.
3. Albano, E., Lott, K.A.K., Slater, T.F., Stier, A., Symons, M.C.R., and Tomasi, A. (1982). Spin-trapping studies on the free-radical products formed by metabolic activation of carbon tetrachloride in rat liver microsomal fractions isolated hepatocytes and in vivo in the rat. Biochem. J. 204, 593-603.
4. Albertini, S. (1990). Analysis of nine known or suspected spindle poisons for mitotic chromosome malsegregation using Saccharomyces cerevisiae D61.M. Mutagenesis 5, 453-459.
5. Allen, J.W., Collins, B.W., and Evansky, P.A. (1994). Spermatid micronucleus analyses of trichloroethylene and chloral hydrate effects in mice. Mutat. Res. 323, 81-88.
6. American Hospital Formulary Service (AHFS) (1999). Drug Information (G.K. McEvoy, Ed.), pp. 2097-2098. American Society of Health-System Pharmacists, Inc., Bethesda, MD.
7. Armitage, P. (1971). Statistical Methods in Medical Research, pp. 362-365. John Wiley and Sons, Inc., New York.
8. Aust, S.D., Chignell, C.F., Bray, T.M., Kalyanaraman, B., and Mason, R.P. (1993). Free radicals in toxicology. Toxicol. Appl. Pharmacol. 120, 168-178.
9. Basu, A.K., O'Hara, S.M., Valladier, P., Stone, K., Mols, O., and Marnett, L.J. (1988). Identification of adducts formed by reaction of guanine nucleosides with malondialdehyde and structurally related aldehydes. Chem. Res. Toxicol. 1, 53-59.
10. Benamira, M., Johnson, K., Chaudhary, A., Bruner, K., Tibbetts, C., and Marnett, L.J. (1995). Induction of mutations by replication of malondialdehyde-modified M13 DNA in Esherichia coli: Determination of the extent of DNA modification, genetic requirements for mutagenesis, and types of mutations induced. Carcinogenesis 16, 93-99.
11. Bergman, K. (1983). Interactions of trichloroethylene with DNA in vitro and with RNA and DNA of various mouse tissues in vivo. Arch. Toxicol. 54, 181-193.
12. Bignami, M. Conti, G., Conti, L., Crebelli, R., Misuraca, F., Puglia, A.M., Randazzo, R., Sciandrello, G., and Carere, A. (1980). Mutagenicity of halogenated aliphatic hydrocarbons in Salmonella typhimurium, Streptomyces coelicolor and Aspergillus nidulans. Chem. Biol. Interact. 30, 9-23.
13. Breimer, D.D., Ketelaars, H.C.J., and Van Rossum, J.M. (1974). Gas chromatographic determination of chloral hydrate, trichloroethanol and trichloroacetic acid in blood and in urine employing head-space analysis. J. Chromatogr. 88, 55-63.
14. Bronzetti, G., Galli, A., Corsi, C., Cundari, E., Del Carratore, R., Nieri, R., and Paolini, M. (1984). Genetic and biochemical investigation on chloral hydrate in vitro and in vivo. Mutat. Res. 141, 19-22.
15. Bruckner, J.V., Davis, B.D., and Blancato, J.N. (1989). Metabolism, toxicity, and carcinogenicity of trichloroethylene. Crit. Rev. Toxicol. 20, 31-50.
16. Bull, R.J., Sanchez, I.M., Nelson, M.A., Larson, J.L., and Lansing, A.J. (1990). Liver tumor induction in B6C3F1 mice by dichloroacetate and trichloroacetate. Toxicology 63, 341-359.
17. Bull, R.J., Templin, M., Larson, J.L., and Stevens, D.K. (1993). The role of dichloroacetate in the hepatocarcinogenicity of trichloroethylene. Toxicol. Lett. 68, 203-211.
18. Cabana, B.E., and Gessner, P.K. (1970). The kinetics of chloral hydrate metabolism in mice and the effect thereon of ethanol. J. Pharmacol. Exp. Ther. 174, 260-275.
19. Chang, L.W., Daniel, F.B., and DeAngelo, A.B. (1992). Analysis of DNA strand breaks induced in rodent liver in vivo, hepatocytes in primary culture, and a human cell line by chlorinated acetic acids and chlorinated acetaldehydes. Environ. Mol. Mutagen. 20, 277-288.
20. Chaudhary, A.K., Nokubo, M., Reddy, G.R., Yeola, S.N., Morrow, J.D., Blair, I.A., and Marnett, L.J. (1994). Detection of endogenous malondialdehyde-deoxyguanosine adducts in human liver. Science 265, 1580-1582.
21. Comporti, M. (1985). Biology of disease. Lipid peroxidation and cellular damage in toxic liver injury. Lab. Invest. 53, 599-623.
22. Costa, A.K., and Ivanetich, K.M. (1984). Chlorinated ethylenes: Their metabolism and effect on DNA repair in rat hepatocytes. Carcinogenesis 5, 1629-1636.
23. Crebelli, R., and Carere, A. (1987). Chemical and physical agents assayed in tests for mitotic intergenic and intragenic recombination in Aspergillus nidulans diploid strains. Mutagenesis 2, 469-475.
24. Crebelli, R., and Carere, A. (1989). Genetic toxicology of 1, 1, 2-trichloroethylene. Mutat. Res. 221, 11-37.
25. Crebelli, R., Conti, G., Conti, L., and Carere, A. (1991). In vitro studies with nine known or suspected spindle poisons: Results in tests for chromosome malsegregation in Aspergillus nidulans. Mutagenesis 6, 131-136.
26. Crespi, C.L., Ryan, C.G., Seixas, G.M., Turner, T.R., and Penman, B.W. (1985). Tests for mutagenic activity using mutation assays at two loci in the human lymphoblast cell lines TK6 and AHH-1. In Progress in Mutation Research; Evaluation of Short-term Tests for Carcinogens; Report of the International Programme on Chemical Safety's Collaborative Study on In vitro Assays (J. Ashby, F.J. de Serres, M. Draper, M. Ishidate, Jr., B.H. Margolin, B.E. Matter, and M.D. Shelby, Eds.), Vol. 5, pp. 497-516. Elsevier Science Publishers, Amsterdam.
27. Daniel, F.B., Robinson, M., Stober, J.A., Page, N.P., and Olson, G.R. (1992a). Ninety-day toxicity study of chloral hydrate in the Sprague-Dawley rat. Drug Chem. Toxicol. 15, 217-232.
28. Daniel, F.B., DeAngelo, A.B., Stober, J.A., Olson, G.R., and Page, N.P. (1992b). Hepatocarcinogenicity of chloral hydrate, 2-chloroacetaldehyde, and dichloroacetic acid in the male B6C3F1 mouse. Fundam. Appl. Toxicol. 19, 159-168.
29. Davidson, I.W.F., and Beliles, R.P. (1991). Consideration of the target organ toxicity of trichloroethylene in terms of metabolite toxicity and pharmacokinetics. Drug Metab. Rev. 23, 493-599.
30. DeAngelo, A.B., and Daniel, F.B. (1990). The comparative carcinogenicity of dichloroacetic (DCA) and trichloroacetic (TCA) acid in the male B6C3F1 mouse. Toxicologist 10, 148.
31. DeAngelo, A.B., and George, M.H. (1995). Evaluation of the carcinogenicity of chloral hydrate in the male B6C3F1 mouse and F344 rat. Proc. Amer. Assoc. Cancer Res. 36, 132 (Abstr.).
32. DeAngelo, A.B., Daniel, F.B., McMillan, L., Wernsing, P., and Savage, R.E., Jr. (1989). Species and strain sensitivity to the induction of peroxisome proliferation by chloroacetic acids. Toxicol. Appl. Pharmacol. 101, 285-298.
33. DeAngelo, A.B., Daniel, F.B., Stober, J.A., and Olson, G.R. (1991). The carcinogenicity of dichloroacetic acid in the male B6C3F1 mouse. Fund. Appl. Toxicol. 16, 337-347.
34. Degrassi, F., and Tanzarella, C. (1988). Immunofluorescent staining of kinetochores in micronuclei: A new assay for the detection of aneuploidy. Mutat. Res. 203, 339-345.
35. Dekant, W., Schulz, A., Metzler, M., and Henschler, D. (1986). Absorption, elimination and metabolism of trichloroethylene: A quantitative comparison between rats and mice. Xenobiotica 16, 143-152.
36. DeMarini, D.M., Brockman, H.E., de Serres, F.J., Evans, H.H., Stankowski, L.F., Jr., and Hsie, A.W. (1989). Specific-locus mutations induced in eukaryotes (especially mammalian cells) by radiation and chemicals: A perspective. Mutat. Res. 220, 11-29.
37. Dunnett, C.W. (1955). A multiple comparison procedure for comparing several treatments with a control. J. Am. Stat. Assoc. 50, 1096-1121.
38. Ekström, T., Garberg, P., Egestad, B., and Högberg, J. (1988). Recovery of malondialdehyde in urine as a 2, 4-dinitrophenylhydrazine derivative analyzed with high-performance liquid chromatography. Chem.-Biol. Interact. 66, 177-187.
39. Elcombe, C.R., Pratt, I.S., and Green, T. (1987). Species differences in biotransformation of and peroxisome proliferation due to trichloroethylene. Arch. Toxicol. (Suppl. 10), 147.
40. Feldman, R.G., Chirico-Post, J., and Proctor, S.P. (1988). Blink reflex latency after exposure to trichloroethylene in well water. Arch. Environ. Health 43, 143-148.
41. Feron, V.J., Til, H.P., de Vrijer, F., Woutersen, R.A., Cassee, F.R., and van Bladeren, P.J. (1991). Aldehydes: Occurrence, carcinogenic potential, mechanism of action and risk assessment. Mutat. Res. 259, 363-385.
42. Fisher, J.W., and Allen, B.C. (1993). Evaluating the risk of liver cancer in humans exposed to trichloroethylene using physiological models. Risk Anal. 13, 87-95.
43. Fisher, J.W., Gargas, M.L., Allen, B.C., and Andersen, M.E. (1991). Physiologically based pharmacokinetic modeling with trichloroethylene and its metabolite, trichloroacetic acid, in the rat and mouse. Toxicol. Appl. Pharmacol. 109, 183-195.
44. Fu, P.P., Von Tungeln, L.S., Unruh, L.E., Ni, Y.-C., and Chou, M.W. (1991). Comparative regioselective and stereoselective metabolism of 7-chlorobenz[a]anthracene and 7-bromobenz[a]anthracene by mouse and rat liver microsomes. Carcinogenesis 12, 371-378.
45. Furnus, C.C., Ulrich, M.A., Terreros, M.C., and Dulout, F.N. (1990). The induction of aneuploidy in cultured Chinese hamster cells by propionaldehyde and chloral hydrate. Mutagenesis 5, 323-326.
46. Furth, E.E., Thilly, W.G., Penman, B.W., Liber, H.L., and Rand, W.M. (1981). Quantitative assay for mutation in diploid human lymphoblasts using microtiter plates. Anal. Biochem. 110, 1-8.
47. Galloway, S.M., Armstrong, M.J., Reuben, C., Colman, S., Brown, B., Cannon, C., Bloom, A.D., Nakamura, F., Ahmed, M., Duk, S., Rimpo, J., Margolin, B.H., Resnick, M.A., Anderson, B., and Zeiger, E. (1987). Chromosome aberrations and sister chromatid exchanges in Chinese hamster ovary cells: Evaluations of 108 chemicals. Environ. Mol. Mutagen. 10 (Suppl. 10), 1-175.
48. Gart, J.J., Chu, K.C., and Tarone, R.E. (1979). Statistical issues in interpretation of chronic bioassay tests for carcinogenicity. JNCI 62, 957-974.
49. Gorecki, D.K.J., Hindmarsh, K.W., Hall, C.A., Mayers, D.J., and Sankaran, K. (1990). Determination of chloral hydrate metabolism in adult and neonate biological fluids after single-dose administration. J. Chromatogr. 528, 333-341.
50. Green, T., and Prout, M.S. (1985). Species differences in response to trichloroethylene. II. Biotransformation in rats and mice. Toxicol. Appl. Pharmacol. 79, 401-411.
51. Guengerich, F.P., Mason, P.S., Stott, W.T., Fox, T.R., Watanabe, P.G. (1981). Roles of 2-haloethylene oxides and 2-haloacetaldehydes derived from vinyl bromide and vinyl chloride in irreversible binding to protein and DNA. Cancer Res. 41, 4391-4398.
52. Hara, A., Yamamoto, H., Deyashiki, Y., Nakayama, T., Oritani, H., and Sawada, H. (1991). Aldehyde dismutation catalyzed by pulmonary carbonyl reductase: Kinetic studies of chloral hydrate metabolism to trichloroacetic acid and trichloroethanol. Biochim. Biophys. Acta 1075, 61-67.
53. Haworth, S., Lawlor, T., Mortelmans, K., Speck, W., and Zeiger, E. (1983). Salmonella mutagenicity test results for 250 chemicals. Environ. Mutagen. Suppl. 5 (Suppl. 1), 3-142.
54. Henderson, G.N., Yan, Z., James, M.O., Davydova, N., and Stacpoole, P.W. (1997). Kinetics and metabolism of chloral hydrate in children: Identification of dichloroacetate as a metabolite. Biochem. Biophys. Res. Commun. 235, 695-698.
55. Henschler, D., Elsässer, H., Romen, W., and Eder, E. (1984). Carcinogenicity study of trichloroethylene, with and without epoxide stabilizers, in mice. J. Cancer Res. Clin. Oncol. 107, 149-156.
56. Herren-Freund, S.L., Pereira, M.A., Khoury, M.D., and Olson, G. (1987). The carcinogenicity of trichloroethylene and its metabolites, trichloroacetic acid and dichloroacetic acid, in mouse liver. Toxicol. Appl. Pharmacol. 90, 183-189.
57. Ikeda, M., Miyake, Y., Ogata, M., and Ohmori, S. (1980). Metabolism of trichloroethylene. Biochem. Pharmacol. 29, 2983-2992.
58. Integrated Laboratory Systems (ILS) (1990). Micronucleus Data Management and Statistical Analysis Software, Version 1.4. ILS, P.O. Box 13501, Research Triangle Park, NC 27707.
59. Jonckheere, A.R. (1954). A distribution-free k-sample test against ordered alternatives. Biometrika 41, 133-145.
60. Juntunen, J. (1986). Occupational toxicology of trichloroethylene with special reference to neurotoxicity. Toxicol. Lett. 31 (Suppl.), 16 (Abstr.).
61. Kallman, M.J., Kaempf, G.L., and Balster, R.L. (1984). Behavioral toxicity of chloral in mice: An approach to evaluation. Neurobehav. Toxicol. Teratol. 6, 137-146.
62. Kauffmann, B.M., White, K.L., Jr., Sanders, V.M., Douglas, K.A., Sain, L.E., Borzelleca, J.F., and Munson, A.E. (1982). Humoral and cell-mediated immune status in mice exposed to chloral hydrate. Environ. Health Perspect. 44, 147-151.
63. Kautiainen, A., Vaca, C.E., and Granath, F. (1993). Studies on the relationship between hemoglobin and DNA adducts of malonaldehyde and their stability in vivo. Carcinogenesis 14, 705-708.
64. Keller, D.A., and Heck, H.d'A. (1988). Mechanistic studies on chloral toxicity: Relationship to trichloroethylene carcinogenesis. Toxicol. Lett. 42, 183-191.
65. Kerns, W.D., Pavkov, K.L., Donofrio, D.J., Gralla, E.J., and Swenberg, J.A. (1983). Carcinogenicity of formaldehyde in rats and mice after long-term inhalation exposure. Cancer Res. 43, 4382-4392.
66. Leopardi, P., Zijno, A., Bassani, B., and Pacchierotti, F. (1993). In vivo studies on chemically induced aneuploidy in mouse somatic and germinal cells. Mutat. Res. 287, 119-130.
67. Leuschner, J., and Beuscher, N. (1998). Studies on the mutagenic and carcinogenic potential of chloral hydrate. Arzneim.-Forsch./Drug Res. 48, 961-968.
68. Liang, J.C., and Pacchierotti, F. (1988). Cytogenetic investigation of chemically-induced aneuploidy in mouse spermatocytes. Mutat. Res. 201, 325-335.
69. Liebler, D.C. (1993). The role of metabolism in the antioxidant function of vitamin E. Crit. Rev. Toxicol. 23, 147-169.
70. Lowry, O.H., Rosebrough, N.J., Farr, A.L., and Randall, R.J. (1951). Protein measurement with the folin phenol reagent. J. Biol. Chem. 193, 265-275.
71. Mailhes, J.B., Preston, R.J., Yuan, Z.P., and Payne, H.S. (1988). Analysis of mouse metaphase II oocytes as an assay for chemically induced aneuploidy. Mutat. Res. 198, 145-152.
72. Mailhes, J.B., Aardema, M.J., and Marchetti, F. (1993). Investigation of aneuploidy induction in mouse oocytes following exposure to vinblastine-sulfate, pyrimethamine, diethylstilbestrol diphosphate, or chloral hydrate. Environ. Mol. Mutagen. 22, 107-114.
73. Margolin, B.H., Collings, B.J., and Mason, J.M. (1983). Statistical analysis and sample-size determinations for mutagenicity experiments with binomial responses. Environ. Mutagen. 5, 705-716.
74. Maron, D.M., and Ames, B.N. (1983). Revised methods for the Salmonella mutagenicity test. Mutat. Res. 113, 173-215.
75. Material Safety Data Sheet Collection (MSDS) (1991). Chloral Hydrate Sheet No. OHS23800. Occupational Health Services, Inc., New York.
76. Mayers, D.J., Hindmarsh, K.W., Sankaran, K., Gorecki, D.K.J., and Kasian, G.F. (1991). Chloral hydrate disposition following single-dose administration to critically ill neonates and children. Dev. Pharmacol. Ther. 16, 71-77.
77. The Merck Index (1989). 11th ed. (S. Budavari, Ed.), p. 317. Merck and Company, Rahway, NJ.
78. Merdink, J.L., Gonzalez-Leon, A., Bull, R.J., and Schultz, I.R. (1998). The extent of dichloroacetate formation from trichloroethylene, chloral hydrate, trichloroacetate, and trichloroethanol in B6C3F1 mice. Toxicol. Sci. 45, 33-41.
79. Miller, B.M., and Adler, I.-D. (1992). Aneuploidy induction in mouse spermatocytes. Mutagenesis 7, 69-76.
80. Natarajan, A.T., Duivenvoorden, W.C.M., Meijers, M., and Zwanenburg, T.S.B. (1993). Induction of mitotic aneuploidy using Chinese hamster primary embryonic cells. Test results of 10 chemicals. Mutat. Res. 287, 47-56.
81. National Cancer Institute (NCI) (1976). Carcinogenesis Bioassay of Trichloroethylene (CAS No. 79-01-6). Technical Report Series No. 2. NIH Publication No. 76-802. U.S. Department of Health, Education, and Welfare, Public Health Service, National Institutes of Health, Bethesda, MD.
82. National Toxicology Program (NTP) (1988). Toxicology and Carcinogenesis Studies of Trichloroethylene (CAS No. 79-01-6) in Four Strains of Rats (ACI, August, Marshall, Osborne-Mendel) (Gavage Studies). Technical Report Series No. 273. NIH Publication No. 88-2529. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Research Triangle Park, NC.
83. National Toxicology Program (NTP) (1990). Carcinogenesis Studies of Trichloroethylene (Without Epichlorohydrin) (CAS No. 79-01-6) in F344/N Rats and B6C3F Mice (Gavage Studies). Technical Report 1 Series No. 243. NIH Publication No. 90-1799. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Research Triangle Park, NC.
84. Nelson, M.A., and Bull, R.J. (1988). Induction of strand breaks in DNA by trichloroethylene and metabolites in rat and mouse liver in vivo. Toxicol. Appl. Pharmacol. 94, 45-54.
85. Nutley, E.V., Tcheong, A.C., Allen, J.W., Collins, B.W., Ma, M., Lowe, X.R., Bishop, J.B., Moore, D.H., II, and Wyrobek, A.J. (1996). Micronuclei induced in round spermatids of mice after stem-cell treatment with chloral hydrate: Evaluations with centromeric DNA probes and kinetochore antibodies. Environ. Mol. Mutagen. 28, 80-89.
86. Odum, J., Green, T., Foster, J.R., and Hext, P.M. (1988). The role of trichloroacetic acid and peroxisome proliferation in the differences in carcinogenicity of perchloroethylene in the mouse and rat. Toxicol. Appl. Pharmacol. 92, 103-112.
87. Omura, T., and Sato, R. (1964). The carbon monoxide-binding pigment of liver microsomes. J. Biol. Chem. 239, 2370-2378.
88. Parry, J.M., and James, S. (1988). The detection of aneugenic chemicals using yeast strain D. Mutagenesis 6 3, 447.
89. Penman, B.W., and Crespi, C.L. (1987). Analysis of human lymphoblast mutation assays by using historical negative control data bases. Environ. Mol. Mutagen. 10, 35-60.
90. Perocco, P., and Prodi, G. (1981). DNA damage by haloalkanes in human lymphocytes cultured in vitro. Cancer Lett. 13, 213-218.
91. Peter, R., Böcker, R., Beaune, P.H., Iwasaki, M., Guengerich, F.P., and Yang, C.S. (1990). Hydroxylation of chlorzoxazone as a specific probe for human liver cytochrome P-450IIE1. Chem. Res. Toxicol. 3, 566-573.
92. Prout, M.S., Provan, W.M., and Green, T. (1985). Species differences in response to trichloroethylene. I. Pharmacokinetics in rats and mice. Toxicol. Appl. Pharmacol. 79, 389-400.
93. Reddy, M.V., and Randerath, K. (1986). Nuclease P1-mediated enhancement of sensitivity of 32P-postlabeling test for structurally diverse DNA adducts. Carcinogenesis 7, 1543-1551.
94. Rijhsinghani, K.S., Abrahams, C., Swerdlow, M.A., Rao, K.V.N., and Ghose, T. (1986). Induction of neoplastic lesions in the livers of C BL × C HF mice by chloral hydrate. Cancer Detect. Prev. 9, 279-288.
95. Roe, F.J.C, and Salaman, M.H. (1955). Further studies on incomplete carcinogenesis: Triethylene melamine (T.E.M.), 1, 2-benzanthracene and $-propiolactone, as initiators of skin tumour formation in the mouse. Br. J. Cancer 9, 177-203.
96. Rossoff, I.S. (1974). Handbook of Veterinary Drugs, pp. 93-94. Springer Publishing Co., New York.
97. Russo, A., and Levis, A.G. (1992). Further evidence for the aneuploidogenic properties of chelating agents: Induction of micronuclei in mouse male germ cells by EDTA. Environ. Mol. Mutagen. 19, 125-131.
98. Russo, A., Paccierotti, F., and Metalli, P. (1984). Nondisjunction induced in mouse spermatogenesis by chloral hydrate, a metabolite of trichloroethylene. Environ. Mutagen. 6, 695-703.
99. Sanders, V.M., Kauffmann, B.M., White, K.L., Jr., Douglas, K.A., Barnes, D.W., Sain, L.E., Bradshaw, T.J., Borzelleca, J.F., and Munson, A.E. (1982). Toxicology of chloral hydrate in the mouse. Environ. Health Perspect. 44, 137-146.
100. Sbrana, I., Di Sibio, A., Lomi, A., and Scarcelli, V. (1993). C-Mitosis and numerical chromosome aberration analyses in human lymphocytes: 10 known or suspected spindle poisons. Mutat. Res. 287, 57-70.
101. Sellakumar, A.R., Snyder, C.A., Solomon, J.J., and Albert, R.E. (1985). Carcinogenicity of formaldehyde and hydrogen chloride in rats. Toxicol. Appl. Pharmacol. 81, 401-406.
102. Shara, M.A., Dickson, P.H., Bagchi, D., and Stohs, S.J. (1992). Excretion of formaldehyde, malondialdehyde, acetaldehyde and acetone in the urine of rats in response to 2, 3, 7, 8-tetrachlorodibenzo-pdioxin, paraquat, endrin and carbon tetrachloride. J. Chromatogr. 576, 221-233.
103. Shelby, M.D., Erexson, G.L., Hook, G.J., and Tice, R.R. (1993). Evaluation of a three-exposure mouse bone marrow micronucleus protocol: Results with 49 chemicals. Environ. Mol. Mutagen. 21, 160-179.
104. Smith, M.K., Randall, J.L., Read, E.J., and Stober, J.A. (1989). Teratogenic activity of trichloroacetic acid in the rat. Teratology 40, 445-451.
105. Smith, M.T. (1990). Chloral hydrate warning. Science 250, 359.
106. Sora, S., and Agostini Carbone, M.L. (1987). Chloral hydrate, methylmercury hydroxide and ethydium bromide affect chromosomal segregation during meiosis of Saccharomyces cerevisiae. Mutat. Res. 190, 13-17.
107. Stone, K., Ksebati, M.B., and Marnett, L.J. (1990). Investigation of the adducts formed by reaction of malondialdehyde with adenosine. Chem. Res. Toxicol. 3, 33-38.
108. Stott, W.T., Quast, J.F., and Watanabe, P.G. (1982). The pharmacokinetics and macromolecular interactions of trichloroethylene in mice and rats. Toxicol. Appl. Pharmacol. 62, 137-151.
109. Uehleke, H., and Poplawski-Tabarelli, S. (1977). Irreversible binding of 14C-labelled trichloroethylene to mice liver constituents in vivo and in vitro. Arch. Toxicol. 37, 289-294.
110. United States Environmental Protection Agency (USEPA) (1982). Chemical Hazard Information Profile. Trichloroacetaldehyde. Environmental Protection Agency, Office of Toxic Substances, Washington, DC. (Draft).
111. Vaca, C.E., Wilhelm, J., and Harms-Ringdahl, M. (1988). Interaction of lipid peroxidation products with DNA. A review. Mutat. Res. 195, 137-149.
112. Vaca, C.E., Vodika, P., and Hemminki, K. (1992). Determination of malondialdehyde-modified 2N-deoxyguanosine-3N-monophosphate and DNA by 32P-postlabelling. Carcinogenesis 13, 593-599.
113. Vaca, C.E., Fang, J.-L., Mutanen, M., and Valsta, L. (1995). 32P-Postlabeling determination of DNA adducts of malonaldehyde in humans: Total white blood cells and breast tissue. Carcinogenesis 16, 1847-1851.
114. Vagnarelli, P., De Sario, A., and De Carli, L. (1990). Aneuploidy induced by chloral hydrate detected in human lymphocytes with the Y97 probe. Mutagenesis 5, 591-592.
115. Wade, A., Ed. (1977). Martindale: The Extra Pharmacopoeia, 27th ed., pp.752-754. The Pharmaceutical Press, London.
116. Walles, S.A.S. (1986). Induction of single-strand breaks in DNA of mice by trichloroethylene and tetrachloroethylene. Toxicol. Lett. 31, 31-35.
117. Waskell, L. (1978). A study of the mutagenicity of anesthetics and their metabolites. Mutat. Res. 57, 141-153.
118. Williams, D.A. (1971). A test for differences between treatment means when several dose levels are compared with a zero dose control. Biometrics 27, 103-117.
119. Williams, D.A. (1972). The comparison of several dose levels with a zero dose control. Biometrics 28, 519-531.
120. Woutersen, R.A., and Feron, V.J. (1987). Inhalation toxicity of acetaldehyde in rats. IV. Progression and regression of nasal lesions after discontinuation of exposure. Toxicology 47, 295-305.
121. Woutersen, R.A., Appelman, L.M., Van Garderen-Hoetmer, A., and Feron, V.J. (1986). Inhalation toxicity of acetaldehyde in rats. III. Carcinogenicity study. Toxicology 41, 213-231.
122. Xu, W., and Adler, I.-D. (1990). Clastogenic effects of known and suspect spindle poisons studied by chromosome analysis in mouse bone marrow cells. Mutagenesis 5, 371-374.
123. Yoon, J.S., Mason, J.M., Valencia, R., Woodruff, R.C., and Zimmering, S. (1985). Chemical mutagenesis testing in Drosophila. IV. Results of 45 coded compounds tested for the National Toxicology Program. Environ. Mutagen. 7, 349-367.
124. Young, J.F., White, C.G., and Pearce, B.A. (1981). A hybrid computer system for pharmacokinetic modeling. II. Applications. In Proceedings 1981 Summer Computer Simulation Conference, pp. 122-129.