Current status of bioassays in genetic toxicology--the dominant lethal assay. A report of the U.S. Environmental Protection Agency Gene-Tox Program.

The term dominant lethal may be defined as death of the heterozygote arising through multiple chromosomal breaks. The assay is generally conducted by treating male animals, usually mice or rats, acutely (1 dose), subacutely (5 doses), or over the entire period of spermatogenesis. Animals treated acutely or subacutely are mated at weekly intervals to females for a sufficient number of weeks to cover the period of spermatogenesis. Those treated for the entire spermatogenic cycle are mated for 1 or 2 successive weeks at the termination of treatment. Females usually are killed at 14 days of pregnancy and examined for the number of total implantations in the uterus, the number of implantations classified as early deaths, and, in some cases, the number of corpora lutea. The category of early death is the most significant index of dominant lethality. A total of 249 papers were reviewed and 140 chemicals were evaluated. Of the 140 chemicals, 65 were positive by the criteria used by the Work Group in evaluating each publication. The category of "positive" includes those responses of a borderline nature. 99 chemicals were declared negative. There is considerable overlap of chemicals in both categories, which accounts for the incongruity in the total number of chemicals tested and the number considered positive and negative. A total of 44 animal carcinogens have been tested in the dominant lethal assay, 26 of which were positive and 18 negative for a correlation of 59%. The role of the assay should be that of confirming positive results from lower tier chromosomal aberration-detecting systems (confirming in the sense of indicating the ability of the chemical to penetrate gonadal tissue and to produce cytogenetic damage). The dominant lethal assay should not be used as a risk assessment method.

[1]  D. G. Gosslee,et al.  Effects of dose on the induction of dominant-lethal mutations and heritable translocations with ethyl methanesulfonate in male mice. , 1974, Genetics.

[2]  G. Kennedy,et al.  Dominant lethal studies with technical chlordane, HCS-3260, and heptachlor: heptachlor epoxide. , 1977, Journal of toxicology and environmental health.

[3]  J. Clark.  Mutagenicity of DDT in mice, Drosophila melanogaster and Neurospora crassa. , 1974, Australian journal of biological sciences.

[4]  E. R. Soares.  Studies of factors influencing the mutagenicity of EMS in mice. , 1976, Mutation research.

[5]  F. Badr,et al.  Studies on the mutagenic effect of contraceptive drugs. I. Induction of dominant lethal mutations in female mice. , 1974, Mutation research.

[6]  R. Sram,et al.  The mutagenic effect of lysergic acid diethylamide. II. Dominant lethal test in mice. , 1974, Mutation research.

[7]  U. Ehling.  Synergistic effect of mitomycin C and radiation on embryonic litter size reduction in mice. , 1971, Mutation research.

[8]  A. R. Singh,et al.  Mutagenic and antifertility sensitivities of mice to di-2-ethylhexyl phthalate (DEHP) and dimethoxyethyl phthalate (DMEP). , 1974, Toxicology and applied pharmacology.

[9]  S. Green,et al.  A more refined approach to dominant lethal testing , 1975 .

[10]  T. Collins.  Dominant lethal assay. II. Folpet and Difolatan. , 1972, Food and cosmetics toxicology.

[11]  H. Jackson,et al.  Antifertility and dominant lethal mutation studies in male rats with dl-alpha-chlorohydrin and an amino-analogue. , 1976, Contraception.

[12]  J. Favor,et al.  EMS-induced dominant lethal dose response curve in DBA/1J male mice. , 1978, Mutation research.

[13]  H. Tezuka,et al.  Mutagenicity testing on ethylenethiourea , 1977 .

[14]  C. Sheu,et al.  Heritable translocation test on random-bred mice after prolonged triethylenemelamine treatment. , 1978, Mutation research.

[15]  F. Serres.  CHEMICAL MUTAGENS: PRINCIPLES AND METHODS FOR THEIR DETECTION , 1972 .

[16]  G. Kennedy,et al.  Dominant lethal studies with alkylating agents: dose-response relationships. , 1976, Toxicology and applied pharmacology.

[17]  J. R. Steelman,et al.  Oral triethylenemelamine: effects in the dominant lethal assay for mutagenicity. , 1977, Toxicology and applied pharmacology.

[18]  T. Collins.  Dominant lethal assay. I. Captan. , 1972, Food and cosmetics toxicology.

[19]  S. Epstein,et al.  The failure of caffeine to induce mutagenic effects or to synergize the effects of known mutagens in mice. , 1970, Food and cosmetics toxicology.

[20]  B. Matter,et al.  Premature chromosome condensation, structural chromosome aberrations, and micronuclei in early mouse embryos after treatment of paternal postmeiotic germ cells with triethylenemelamine: possible mechanisms for chemically induced dominant-lethal mutatiions. , 1975, Mutation research.

[21]  P. Propping,et al.  Mutagenic activity of isoniazid and hydrazine in mammalian test systems. , 1972, Mutation research.

[22]  H. Hummler,et al.  A comparative study on the mutagenicity of ethylenethiourea in bacterial and mammalian test systems , 1977 .

[23]  F. Figge,et al.  Dominant-lethal effects of cyclohexylamine in C57 B1-Fe mice. , 1972, Mutation research.

[24]  C. Reddy,et al.  Teratogenic and dominant lethal studies of patulin in mice. , 1978, Toxicology.

[25]  J. Kratochvílová.  Evaluation of pre-implantation loss in dominant-lethal assay in the mouse. , 1978, Mutation research.

[26]  A. Bateman,et al.  Dominant lethal mutations induced in male mice by methyl methanesulphonate , 1964, Heredity.

[27]  B. J. Dean,et al.  Dominant lethal assays in male mice: evaluation of experimental design, statistical methods and the sensitivity of Charles River (CD1) mice. , 1977, Mutation research.

[28]  D. Villeneuve,et al.  Mirex: a teratogenicity, dominant lethal and tissue distribution study in rats. , 1976, Food and cosmetics toxicology.

[29]  F. Sauro,et al.  Lack of dominant lethality in rats treated with polychlorinated biphenyls (Aroclors 1242 and 1254). , 1975, Food and cosmetics toxicology.

[30]  U. Ehling.  Comparison of radiation-and chemically-induced dominant lethal mutations in male mice. , 1971, Mutation research.

[31]  J. Bootman,et al.  Mutagenic activity of propylene oxide in bacterial and mammalian systems. , 1979, Mutation research.

[32]  M. M. Varma,et al.  Mutagenicity Following Administration of Dimethyl Mercury in Swiss Male Mice , 1974 .

[33]  M. Lyon,et al.  The mutagenic effect of triethylenemelamine (tem) on germ cells of male golden hamsters and guinea pigs. , 1975, Mutation research.

[34]  K. Řežábek,et al.  Absence of noxious effects of selected neuroleptics in dominant-lethal mutagenesis assay. , 1979, Mutation research.

[35]  R. Sram,et al.  Effect of the dose-fractionation on the frequency of chromosome aberrations induced in mice by TEPA. , 1973, Folia biologica.

[36]  A. Leonard,et al.  Mutagenicity tests with phenylbutazone in mammals , 1978 .

[37]  M. Hyneck,et al.  A study of triflupromazine in dominant-lethal, cytogenetic and host-mediated assays. , 1973, Mutation research.

[38]  J. Clark.  The mutagenicity of azathioprine in mice, Drosophila melanogaster and Neurospora crassa. , 1975, Mutation research.

[39]  J. G. Brewen,et al.  Studies on chemically induced dominant lethality. I. The cytogenetic basis of MMS-induced dominant lethality in post-meiotic male germ cells. , 1975, Mutation research.

[40]  L. Goldstein.  Methyl methanesulfonate-induced dominant lethal mutations in male mice detected in vitro. , 1977, Mutation research.

[41]  M. Legator,et al.  Dominant lethal study of p,p'-DDT in rats. , 1973, Food and cosmetics toxicology.

[42]  J. Crenshaw,et al.  Dominant lethal mutations induced in mice by orally administered ethyl methanesulfonate. , 1974, Mutation research.

[43]  J. Winston,et al.  A dominant lethal study in male rats after repeated exposures to vinyl chloride or vinylidene chloride. , 1977, Journal of toxicology and environmental health.

[44]  F. Badr,et al.  Induction of dominant lethal mutation in male mice by ethyl alcohol , 1975, Nature.

[45]  W. Sheridan,et al.  Triethylenemelamine induced dominant lethals in mice--comparisons of oral versus intraperitoneal injection. , 1977, Mutation research.

[46]  I. Purchase,et al.  Vinyl chloride: dominant lethal studies in male CD-1 mice. , 1976, Mutation research.

[47]  B. Cattanach,et al.  Mutagenicity tests with cyclohexylamine in the mouse. , 1971, Mutation research.

[48]  J. G. Brewen,et al.  6-mercaptopurine, an inducer of cytogenetic and dominant-lethal effects in premeiotic and early meiotic germ cells of male mice. , 1975, Mutation research.

[49]  S. Epstein,et al.  Dominant Lethal Mutations in Mammals , 1971 .

[50]  U. Ehling.  Differential spermatogenic response of mice to the induction of mutations by antineoplastic drugs. , 1974, Mutation research.

[51]  R. Sram.  Relationship between acute and chronic exposures in mutagenicity studies in mice. , 1976, Mutation research.

[52]  S S Epstein,et al.  Detection of chemical mutagens by the dominant lethal assay in the mouse. , 1972, Toxicology and applied pharmacology.

[53]  G. Kennedy,et al.  Reproductive, teratologic, and mutagenic studies with some polydimethylsiloxanes. , 1976, Journal of toxicology and environmental health.

[54]  M. Gallo,et al.  The dominant lethal effect of dietary triethylenemelamine. , 1976, Mutation research.

[55]  J. Corbett,et al.  Dominant lethal mutagenicity study on hair dyes. , 1978, Journal of Toxicology and Environmental Health, Part A.

[56]  A. Bateman.  The induction of dominant lethal mutations in rats and mice with triethylenemelamine (tem). , 1960 .

[57]  M. Hyneck,et al.  A comparative study on the genetic effects of hycanthone and oxamniquine. , 1975, Journal of toxicology and environmental health.

[58]  W. Generoso,et al.  Chemical induction of presumed dominant-lethal mutations in postcopulation germ cells and zygotes of mice. II. Sensitivity of different postcopulation-precleavage stages to three alkylating chemicals. , 1976, Mutation research.

[59]  M. Lyon,et al.  Reproductive capacity and dominant lethal mutations in female guinea-pigs and Djungarian hamsters following X-rays or chemical mutagens. , 1979, Mutation research.

[60]  I. Purchase,et al.  Dominant lethal studies with paraquat and diquat in male CD-1 mice. , 1976, Mutation research.

[61]  Y. Kikuchi,et al.  Chromosome aberrations and dominant lethality of mouse embryos after paternal treatment with triethylenemelamine. , 1977, Mutation research.

[62]  D. Blair,et al.  Dominant lethal assay in female mice after oral dosing with dichlorvos or exposure to atmospheres containing dichlorovos. , 1976, Mutation research.

[63]  W. Generoso,et al.  Tests on induction of chromosome aberrations in mouse germ cells with sodium bisulfite. , 1978, Mutation research.

[64]  M. Lyon,et al.  Failure of mercaptoethylamine to protect against the mutagenic effects of radiation. II. Experiments with mice. , 1953, Science.

[65]  A. R. Singh,et al.  Dominant lethal mutations and antifertility effects of di-2-ethylhexyl adipate and diethyl adipate in male mice. , 1975, Toxicology and applied pharmacology.

[66]  B. J. Dean,et al.  The potential mutagenicity of dieldrin (HEOD) in mammals. , 1975, Food and cosmetics toxicology.

[67]  S. Epstein,et al.  Mutagenicity of Trimethylphosphate in Mice , 1970, Science.

[68]  C. Sheu,et al.  Mutagenicity studies of R-amino salt, a metabolite of amaranth (FD & C Red NO. 2), in mouse lymphoma cells heterozygous at the thymidine kinase locus and in the rat dominant lethal test. , 1979, Food and cosmetics toxicology.

[69]  J. Ruddick,et al.  Polychlorodibenzo-p-dioxins: Perinatal Effects and the Dominant Lethal Test in Wistar Rats , 1973 .

[70]  Rao Ms,et al.  Induction of dominant lethals in mice by sodium saccharin. , 1972 .

[71]  Actions of an antispermatogenic, but non-mutagenic, indenopyridine derivative in mice and Salmonella typhimurium. , 1979, Mutation research.

[72]  A. Leonard,et al.  Mutagenicity tests with cadmium in the mouse. , 1975, Toxicology.

[73]  H. Malling,et al.  Differential spermatogenic response of mice to the induction of dominant-lethal mutations by n-propyl methanesulfonate and isopropyl methanesulfonate. , 1972, Mutation research.

[74]  D. Mackintosh,et al.  Mutagenic and antifertility effects of TEPA and METEPA in mice. , 1970, Toxicology and applied pharmacology.

[75]  R. Cumming,et al.  Induction of dominant lethal mutations by alkylating agents in male mice. , 1968, Mutation research.

[76]  W. Flamm,et al.  A new approach to dominant lethal testing. , 1977, Toxicology and applied pharmacology.

[77]  A. Bateman.  Testing Chemicals for Mutagenicity in a Mammal , 1966, Nature.

[78]  W. Generoso,et al.  Relative rates at which dominant-lethal mutations and heritable translocations are induced by alkylating chemicals in postmeiotic male germ cells of mice. , 1979, Genetics.

[79]  D. Lorke,et al.  Studies of oogenesis and embryogenesis ☆: Experiences with the dominant lethal test in female mice: Effects of alkylating agents and artificial sweetners on pre-ovulatory oocyte stages , 1975 .

[80]  W. Generoso,et al.  Effects of dose on the induction of dominant-lethal mutations with triethylenemelamine in male mice. , 1974, Genetics.

[81]  S. Green,et al.  Dominant lethal assay of some hair-dye components in random-bred male rats. , 1979, Mutation research.

[82]  W. Generoso.  Chemical induction of dominant lethals in female mice. , 1969, Genetics.

[83]  Jean Moutschein.  Mutagenesis with methyl methanesulfonate in mouse. , 1969 .

[84]  B. Cattanach.  The effect of triethylene-melamine on the ferility of female mice. , 1959, International journal of radiation biology and related studies in physics, chemistry, and medicine.

[85]  S. Teramoto,et al.  Induction of dominant-lethal mutations after administration of ethylenethiourea in combination with nitrite of the n-nitroso-ethylenethiourea in mice. , 1978, Mutation research.

[86]  K. S. Khera.  Reproductive capability of male rats and mice treated with methyl mercury. , 1973, Toxicology and Applied Pharmacology.

[87]  R. Sotomayor,et al.  Delayed formation of chromosome aberrations in mouse pachytene spermatocytes treated with triethylenemelamine (TEM). , 1977, Genetics.

[88]  W. Generoso,et al.  Chemically induced dominant-lethal mutations and cell killing mouse oocytes in the advanced stages of follicular development. , 1971, Mutation research.

[89]  J. R. Beall.  Dominant lethal study of the antiandrogen α,α,α-trifluoro-2-methyl-4′-nitro-m-propionotoluidide: A comparison of statistical methods , 1974 .

[90]  R. Sram,et al.  Induction of dominant lethals in mice by TEPA and HEMPA. , 1970, Folia biologica.

[91]  H. Milon,et al.  Caffeine concentrations in mice plasma and testicular tissue and the effect of caffeine on the dominant lethal test. , 1978, Mutation research.

[92]  R. Harbison,et al.  Prenatal toxicity of rubratoxin B and its hydrogenated analog. , 1977, Toxicology and applied pharmacology.

[93]  W. Russell,et al.  Strain and sex variations in the sensitivity of mice to dominant-lethal induction with ethyl methanesulfonate. , 1969, Mutation research.

[94]  I. Hansmann,et al.  Oral contraceptives and chromosome segregation in oocytes of mice. , 1974, Mutation research.

[95]  M. Hite,et al.  Mutagenic evaluation of ronidazole. , 1976, Mutation research.

[96]  M. Roberfroid,et al.  Mutagenicity tests with styrene oxide in mammals. , 1978, Mutation research.

[97]  K. Petersen,et al.  Dominant lethal effects of triflupromazine in hybrid C3D2F 1 -J mice. , 1973, Mutation research.

[98]  J. Borzelleca,et al.  Failure of hexachlorobenzene to induce dominant lethal mutations in the rat. , 1979, Toxicology and applied pharmacology.

[99]  A. Páldy,et al.  The mutagenic effect of a dinitro-o-cresol-containing pesticide on mice germ cells. , 1978, Ecotoxicology and environmental safety.

[100]  Frederick Mosteller,et al.  Tables of the Freeman-Tukey Transformations for the Binomial and Poisson Distributions , 1961 .

[101]  F. Sauro,et al.  Effects of hycanthone on spermatogonial cells, deoxyribonucleic acid synthesis in bone marrow and dominant lethality in rats. , 1973, The Journal of pharmacology and experimental therapeutics.

[102]  C. Hine,et al.  The mutagenic potential of ethylene oxide using the dominant--lethal assay in rats. , 1977, Toxicology and applied pharmacology.

[103]  A. Pasi,et al.  Assessment of the mutagenic properties of diquat and paraquat in the murine dominant lethal test. , 1974, Mutation research.