Hans L. Falk

Teratogenic Evaluation of 2,4,5-T

The herbicide 2,4,5-trichlorophenoxyacetic acid is teratogenic and fetocidal in two strains of mice when administered either subcutaneously or orally and in one strain of rats when administered orally. The incidences of both cystic kidney and cleft palate were increased in the C57BL/6 mice as well as the incidence of cleft palate in the AKR mice. The incidence of cystic kidney was also increased in the rats. In addition, an increase in the ratio of liver weight to body weight in the mouse fetus and the occurrence of hemorrhagic gastrointestinal tract in the rat fetus suggest that this compound also has fetotoxic properties.

Environmental Carcinogens: The Modifying Effect of Cocarcinogens on the Threshold Response

The acceleration of tumor production in mice by repeated application of polycyclic aromatic hydrocarbon carcinogens of high and low potency in the presence of cocarcinogenic compounds is described. Experiments exploring the concentration levels of carcinogen and cocarcinogen necessary to produce tumors demonstrate that there is a 1,000-fold increase in the enhancement of potency of low concentrations of benzo[a]pyrene and benz[a]anthracene when n-dodecane is the diluent. The effect of cocarcinogens is most obvious during exposure to low concentrations of carcinogen. The implications of this observation in the environment is discussed.

Mouse leukemia virus activation by chemical carcinogens.

The induction of lymphomas in C57BL mice by methylcholanthrene, urethan, or diethylnitrosamine was accompanied by the development of murine leukemia viral antigen in most of the lymphoid tumors. The cell-free transmission of lymphomas induced by methylcholanthrene and the development of antibody to murine leukemia virus prior to the detection of overt lymphoma in these mice suggest that unmasking of a latent leukemia virus is an indigenous actuating cause of the lymphomas.

Chromatography of mold metabolites. I. Aflatoxins, ochratoxins and related compounds.

Abstract We have reviewed the literature describing the chromatography of various mold metabolites of major importance as potential health hazard for man ( e.g. , aflatoxins, ochratoxins) and have stressed procedures for their isolation, identification and study of their metabolic pathways.

Uracil Mustard: A Potent Inducer of Lung Tumors in Mice

Uracil mustard, injected intraperitoneally, increased the incidence and average number of pulmonary tumors in A/J mice. In comparison to a typical alkylating agent, nitrogen mustard, or to urethan, uracil mustard (on a molar basis) was considerably more carcinogenic.

Chemical, Physical, and Genetic Factors Interfering with DNA Repair-a Review

Because of its function as transmitter of genetic information, DNA is the most important macromolecule in need of protection from attack by chemical and physical agents, but mechanisms have evolved for repairing such damage to DNA. The presence of the adaptive response and other cellular repair systems (excision, post-replication, SOS, etc.) diminishes the toxicologic effects of low doses of toxic or muta-genic substances. Whether or not these genotoxic effects can be reduced to undetectable levels is not certain. Nonetheless, this repair-mediated diminution of damage due to chemicals constitutes one of the arguments in favor of existence of “safe” threshold levels of chemical exposure (Schendel, 1981). In turn, the repair process itself may be affected by chemical and physical agents. To determine the mode of action of a specific compound on the process of DNA repair becomes complex when all factors are taken into consideration. There are agents which interfere with DNA repair but they are also as active or more active in suppressing replicative DNA synthesis, as well as RNA and protein synthesis. The interference with repair may arise from other major processes such as alteration of energy metabolism and effects on precursor pathways and/or enzymatic cofactors. Whether or not an agent can specifically inhibit DNA repair enzymes has not been answered. The point must be made, however, that this type of interference with essential protective mechanisms is taking place and it may change anticipated outcomes of chemical or physical exposures. The magnitude of this effect due to the exposure of people to so many chemicals should be recognized and studied for their degree of interference with all the processes of DNA repair.

Chromatography of alkylating agents: II. Nitrosamines, epoxides, lactones, methanesulfonates and miscellaneous derivatives

Abstract We have focused on the major areas of varied chromatographic procedures for the analyses primarily of a broad spectrum of alkylating agents (e.g., nitrosamines, epoxides, lactones, methanesulfonates, and miscellaneous agents such as nitrosoureas, urethanes and guanidines, as well as pyrrolizidine alkaloids). A similar treatment was extended to related but non-alkylating agents such as long-chain lactones and pesticidal epoxides. Particular stress was placed on the salient role of chromatographic procedures in the elaboration of compound homogeneity, metabolism, degradation and mode of action of these agents, with particular relevance to the environmental aspects.

Chromatography of alkylating agents: I. Aziridines, nitrogen and sulfur mustards and related derivatives

Abstract We have attempted to stress the major areas of diverse chromatographic procedures for the analyses of a broad spectrum of alkylating agents and related derivatives. Chromatographic analyses have played a singularly important role in the elaboration of compound homogeneity, metabolism, degradation and mode of action of these agents. This aspect is to importance in the light of the anticipated increase in the utility of a variety of alkylating agents, e.g. , chemosterilant aziridines.