Distinguishing potential sources of genotoxic exposure via HPRT mutations.

We utilize T-cell HPRT mutations to monitor exposure to environmental mutagens in siblings of children who have developed cancer at a persistently high rate in Toms River, New Jersey, U.S.A. A preliminary epidemiological study has found a statistically-significant association between drinking public water (by pregnant mother or infant) and subsequent risk for childhood cancer. Three potential sources of mutagenic exposures in Toms River may have increased the rate of carcinogenic initiation significantly in children: 1. Benzidine-based, other azo dye and anthraquinone dye wastes released by Ciba-Geigy, 2. Styrene-acrylonitrile (SAN) trimer and other plastic wastes of Union Carbide, and 3. Radium-224, present in unusually high concentrations in the Cohansey aquifer. Specific patterns of HPRT mutations are utilized to distinguish these various potential sources of carcinogenic exposures in the drinking water of families with childhood cancer and to differentiate chemically or radiologically induced cancers from those which occur spontaneously.

In vivo tissue dosimetry as a basis for cross-species extrapolation in cancer risk assessment of propylene oxide.

The potential for causing carcinogenic and mutagenic effects has been the main concern when assessing the risks associated with low-level exposures of humans to the industrially important epoxide, propylene oxide (PrO). For regulatory purposes, surface-based extrapolation has been used to determine the human equivalent dose from cancer data obtained in rodents. In this context the tissue dose will more adequately reflect inter- and intraspecies differences with respect to pharmacokinetic parameters than is the case for conventional representations of exposure. The formation of adducts in nucleophilic molecular targets by directly acting electrophilic agents, like epoxides, is thought to be closely linked to the process of cancer initiation. To investigate whether tissue dose is correlated to surface area of the exposed organism, the in vivo adduct levels in hemoglobin and DNA have been determined in mice, rats, and dogs after exposure to PrO by injection as well as by inhalation. The results obtained indicate that the dose in blood is virtually the same in the three investigated animal species, whereas surface-area based extrapolation predicts a difference by a factor of about seven between the mouse and the dog. Although the data base is more limited, this conclusion is also supported by measurements of DNA alkylation is selected tissues. The variations actually observed are not related to the surface area of the animal. No significant differences could be found between administration of PrO by injection or by inhalation. For this reason, the surface-based extrapolation model for estimation of the human equivalent dose is not appropriate, and the carcinogenic potency factors for PrO as previously derived by the U.S. EPA should probably be revised downward by a factor of 10 to 13.

Quantitative assessment of a human carcinogenic potency for propylene oxide.

The potential for causing carcinogenic and mutagenic effects is the main concern when assessing the risks associated with low-level exposures of humans to the industrially important epoxide, propylene oxide (PO). The available basic information used in estimation of carcinogenic risk has been reviewed. It is concluded that the published data from gavage studies in rodents are less appropriate and that observed cancer incidences from long-term inhalation should preferably be utilized for quantitative risk assessment. Furthermore, PO and ethylene oxide (EO) are directly acting alkylating agents which exhibit several similarities. Although data are less comprehensive for PO than for EO, PO appears to yield a rather uniform alkylation pattern in various tissues. Also, similarly to EO, PO is probably detoxified at a rate which does not vary widely in various mammalian species, including man. For these reasons, the surface-based extrapolation model for estimation of the human equivalent dose may not be appropriate, and the previously derived carcinogenic potency factors should be revised downward. Alternative risk estimates are provided. From the most relevant available studies, we propose a carcinogenic potency factor of 0.001 (mg/kg/day)-1 for PO in humans by inhalation.

Extragenic suppression of two ribosomal protein cistrons lying near the rif locus in Escherichia coli.

The experiments reported here involve temperature-sensitive mutations in two of five cistrons encoding 50S ribosomal proteins that lie near the rif locus in Escherichia coli. I selected spontaneous TS+ mutants able to grow at elevated temperatures in which the TS+ event takes place outside this tract of cistrons near rif. Six distinct classes of extragenic suppressors were found, five of which have been mapped. Two of these suppressors lie near 64 min, a region known to be rich in cistrons ribosomal proteins (Dennis and Nomura, 1975). The remaining three extragenic suppressors were located near 16.5, 47, and 86 min.

Temperature-sensitive RNA polymerase mutants with altered subunit synthesis and degradation.

A temperature-sensitive mutant having a lethal mutation in the gene for the beta subunit of RNA polymerase (nucleosidetriphosphate:RNA nucleotidyltransferase, EC 2.7.7.6) exhibits an apparent 2- to 3-fold decrease in the rates of both beta and beta' subunit synthesis at the non-permissive temperature, relative to total protein. In contrast, a temperature-sensitive mutant with a lethal mutation in the gene encoding beta' has a 5- to 6-fold increase in the rates of beta and beta' synthesis at 42 degrees. These beta and beta' mutants also exhibit rapid degradation of both subunits at the high temperature.

Host-controlled restriction of T-even bacteriophages: relation of endonuclease I and T-even-induced nucleases to restriction.

Restriction of nonglucosylated T2 phage (T(*)2) as a function of bacterial growth state was the same for endonuclease I-containing and endonuclease I-deficient strains of Escherichia coli B. Furthermore, E. coli strains with various levels of restriction for T2 had comparable endonuclease I activities. It was also found that a T4 mutant temperature-sensitive for gene 46 and 47 functions was fully restricted at 42 C. It therefore appears that neither endonuclease I nor the phage-induced nucleases whose activities are blocked by mutations in genes 46 and 47 catalyze the initial event in restriction of nonglucosylated T-even phages.