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Biomedical subjects

T H Connor

Publications and source records attributed to T H Connor.

At least 19 recordsLinked to original sources
PubMed1999

Surface contamination with antineoplastic agents in six cancer treatment centers in Canada and the United States.

The level of contamination by antineoplastic agents in drug preparation and administration areas in cancer treatment centers in Canada and the United States was determined. Sampling locations at three cancer treatment centers in Canada and three centers in the United States were selected (biological safety cabinets, countertops, and floors in and adjacent to preparation areas; tabletops, chairs, and floors in administration areas). A solution of sodium hydroxide (0.03 M) was spread over the surface of each area. The surface was wiped with one or two absorbent tissues, which were then stored in plastic screw-top containers. Samples were stored at -40 degrees C before analysis of ifosfamide content (U.S. centers only) and cyclophosphamide content by gas chromatography in tandem with mass spectroscopy-mass spectroscopy and fluorouracil content by reverse-phase high-performance liquid chromatography with ultraviolet-light detection. Measurable amounts of the antineoplastic agents were detected in 75% of the pharmacy samples and 65% of the administration samples. In general, the levels of contamination were higher in the pharmacy areas than in the drug administration areas. The pharmacy area at the site with the highest number of drug preparations had considerably more drug contamination than the other sites. The results were similar for Canadian and U.S. centers. Substantial levels of contamination from three antineoplastic agents were detected on a variety of surfaces in pharmacy drug preparation areas and drug administration areas in six cancer treatment centers in Canada and the United States.

Antineoplastic Agents↗
PubMed1999

Detection of ozone-induced DNA single strand breaks in murine bronchoalveolar lavage cells acutely exposed in vivo.

Single-strand breaks (SSBs) in DNA have been used a biomarker of oxidative damage. The comet assay, also known as single-cell gel electrophoresis, was used to investigate the ability of ozone (O(3)) to induce DNA SSBs in murine bronchoalveolar lavage (BAL) cells. The comet assay is more sensitive than other techniques currently utilized for detecting SSBs and requires fewer cells. In the present study, 3 mice were exposed for 3 h to 0.25 ppm of O(3), and 3 to 0.5 ppm of O(3) for 3 h. Two air-exposed mice served as negative controls. All mice were euthanized 3 h after exposure, at which time BAL cells were recovered from the lungs and stained with ethidium bromide. BAL cells recovered from an air-exposed mouse were exposed to various concentrations of H(2)O(2) in vitro for 1 h at 4 degrees C. Excluding cells from the H(2)O(2) group (n = 25), 50 randomly selected BAL cells were graded by comet tail length into 1 of 4 categories: no damage (0 mm), low damage (1-10 mm), medium damage (11-30 mm), and high damage (31 + mm). The nonparametric Wilcoxon rank-sum test was used for statistical analysis, and p values lower than .05 were considered significant. The H(2)O(2) and the 0.25 and 0.5 ppm O3 groups showed statistically significant increases in DNA SSBs as compared to air-exposed controls. The results of this study indicate that (1) O(3) induces DNA strand breaks in murine BAL cells at 0.25 and 0.5 ppm, as evidenced by statistically significant increases in the length of comet tails for O(3)-exposed groups, and (2) the comet assay can be used to assess O(3)-induced SSBs for in vivo exposures. Therefore, it has the potential as a biomarker for in vivo oxidant exposures.

Animals↗
PubMed1996

Monitoring occupational exposure to cancer chemotherapy drugs.

Reports of the health effects of handling cytotoxic drugs and compliance with guidelines for handling these agents are briefly reviewed, and studies using analytical and biological methods of detecting exposure are evaluated. There is little conclusive evidence of detrimental health effects from occupational exposure to cytotoxic drugs. Work practices have improved since the issuance of guidelines for handling these drugs, but compliance with the recommended practices is still inadequate. Of 64 reports published since 1979 on studies of workers' exposure to these drugs, 53 involved studies of changes in cellular or molecular endpoints (biological markers) and 12 described chemical analyses of drugs or their metabolites in urine (2 involved both, and 2 reported the same study). The primary biological markers used were urine mutagenicity, sister chromatid exchange, and chromosomal aberrations; other studies involved formation of micronuclei and measurements of urinary thioethers. The studies had small sample sizes, and the methods were qualitative, nonspecific, subject to many confounders, and possibly not sensitive enough to detect most occupational exposures. Since none of the currently available biological and analytical methods is sufficiently reliable or reproducible for routine monitoring of exposure in the workplace, further studies using these methods are not recommended; efforts should focus instead on wide-spread implementation of improved practices for handling cytotoxic drugs.

Antineoplastic Agents↗
PubMed1996

Mutagenicity of cosmetic products containing Kathon.

A variety of shampoos, conditioners, skin-care lotions, and other cosmetic products contain the biocide Kathon CG, which is a mixture of two heterocyclic isothiazolinones: methylisothiazolinone and methylchloroisothiazolinone. This mixture and the related biocide, Kathon 886, have been shown to be potent sensitizers and bacterial mutagens. Five cosmetic products that list the components of Kathon on their labels and two that do not were screened for mutagenicity with Salmonella typhimurium TA100 without S-9. Five of these products and Kathon 886 were further evaluated in TA100 without and with S-9. Kathon 886, a cosmetic product that contained Kathon, and thin layer chromatography-separated components of Kathon 886 were identified by GC/MS analysis. Three of the five products that listed Kathon were direct acting mutagens with TA100. The remaining two products were considerably more toxic than the other products and could not be evaluated for mutagenicity. The addition of S-9 reduced toxicity but did not eliminate mutagenicity. The mutagenic evaluation of Kathon 886 resulted in a dose response similar to that seen with some cosmetic products but at a 1,000-fold lower concentration, and activity was also reduced by the addition of S-9 mix. S-9 reduced activity both with and without cofactors present. Thin layer chromatography separation of the components and subsequent identification by GC/MS indicated that methylisothiazolinone was nonmutagenic while methylchloroisothiazolinone was mutagenic. Additionally, a dichlorinated compound was identified which was also mutagenic. In light of these findings and the reported skin sensitization by Kathon CG in various cosmetics, we recommend that additional testing be done to assure the safety of products containing Kathon CG.

Chromatography, Thin Layer↗
PubMed1996

Survival of cells with bleomycin-induced chromosomal lesions in the cultured lymphocytes of lung cancer patients.

In a previous study of lung cancer, we showed that bleomycin, a radiomimetic agent, induced breaks preferentially on chromosomes 4 and 5. The molecular cytogenetic study reported here, using chromosome painting and G banding, was designed to assess whether the chromatid breaks induced by bleomycin could survive as chromosome-type aberrations after treated lymphocyte populations were allowed to recover in a drug-free medium for one or two cell generations and whether the survival rates of lesions on chromosomes 4 and 5 differed in cases with lung cancer and controls. The findings from 16 cases and 14 controls showed that in samples allowed to recover for 48 h, most aberrations were of the chromosome type. The proportion of chromosome 5 abnormalities surviving as chromosome-type aberrations was significantly higher in the cells of lung cancer cases (13.4%) than in controls (4.6%; P < 0.0001). However, no significant differences in survival of chromosome 4 abnormalities were detected between cases and controls. The proportions of chromosome 5q13-q22 abnormalities were 5.3% in the cases and 0.6% in the controls (P < 0.0001). 5q13-q22 regions encompassed 38.4% of all abnormalities on chromosome 5 in the cases but only 14.5% in the controls. Therefore, the survival rate of chromosome 5 lesions (especially those at 5q13-q22) in lymphocytes might be used as a biomarker to identify populations at high risk for lung cancer.

Antibiotics, Antineoplastic↗
PubMed1993

Degradation and inactivation of antitumor drugs.

Chemical methods for the degradation of 11 antineoplastic drugs [etoposide, teniposide, bleomycin, mitomycin C, cisplatin, cis-dichloro-trans-dihydroxy-bis(isopropylamine) platinum IV (CHIP), cyclophosphamide, ifosfamide, carmustine, lomustine, and methotrexate] were investigated. The success of the degradation procedures was assessed by HPLC and degree of biological inactivation by mutagenicity assays. The most widely applicable procedure was oxidation with potassium permanganate or 5.25% sodium hypochlorite solution (bleach). Oxidation completely degraded and inactivated etoposide, teniposide, bleomycin, mitomycin C, and methotrexate. In addition, oxidation followed by nucleophilic substitution resulted in the complete degradation and inactivation of cyclophosphamide and ifosfamide. Although carmustine and lomustine were chemically degraded by treatment with acidic potassium permanganate, the resulting reaction mixtures remained mutagenic. Therefore, this procedure cannot be recommended. The platinum-containing compounds, cisplatin and CHIP, were rendered nonmutagenic by reaction with sodium diethyldithiocarbamate. These easily performed, relatively safe procedures can be used to prevent exposure to mutagenic wastes and spills in the hospital setting.

Antineoplastic Agents↗
PubMed1992

Pentamidine isethionate is negative in tests for microbial mutagenicity and chromosomal breakage in vitro.

Pentamidine isethionate, a drug used for the treatment of Pneumocystis carinii pneumonia in AIDS patients, was assayed for mutagenicity in five strains of Salmonella typhimurium and for clastogenicity and mutagen-induced chromosomal breakage in five human lymphoblastoid cell lines. The mutagenicity assay employed both repair-deficient and repair-positive strains without and with the addition of rat liver S-9. There was no indication of a mutagenic response in any of the strains of Salmonella. Chromosomal breakage was measured in lymphoblastoid cell lines, both in the absence and presence of bleomycin. Following 2, 5 and 24 h of treatment, pentamidine alone did not induce clastogenicity, nor was there an increase in chromosomal breakage when the cell lines were treated with bleomycin simultaneously with, or 22 h prior to, the addition of pentamidine. From these data it can be concluded that pentamidine is not mutagenic or clastogenic in the two assays employed in this study.

Animals↗
PubMed1990

Reduction of the mutagenicity of lead chromate-based pigments by encapsulation with silica.

13 lead chromate-based pigments were assayed for mutagenicity and toxicity using Salmonella typhimurium TA100. The compounds were assayed with and without S9, both in the presence and absence of the chelating agent, nitrilotriacetic acid (NTA). In general, the use of NTA to solubilize the compounds resulted in mutagenicity and/or toxicity being observed where it had not in the absence of NTA, or being observed at lower concentrations than when water alone was used. Encapsulation of pigments with amorphous silica rendered these pigments non-mutagenic and non-toxic, indicating that the active moieties were biologically unavailable to the bacteria. Varying the percentage of silica encapsulation on one pigment, medium chrome yellow, indicated that 5% encapsulation did not alter the mutagenicity while 10% encapsulation inhibited the mutagenicity without or with NTA.

Animals↗
PubMed1989

Genotoxic effects of fly ash in bacteria, mammalian cells and animals.

The increasing use of fossil fuels has raised concerns about possible deleterious health effects of the final combustion product, fly ash. Seven ash samples from coal sources obtained from Battelle Columbus Laboratories were evaluated in the Salmonella/mammalian microsome mutagenicity assay to determine their mutagenic potential. While dimethyl sulfoxide extracts of five samples showed no mutagenicity, sample 102 caused an increase in the number of revertants per plate over controls in TA100 and TA98 with activation by liver homogenate (2-fold and 2.4-fold, respectively), and without (2-fold and 6-fold). This ash was thus evaluated in whole animal studies. Animals treated by inhalation or oral gavage were assayed for the presence of mutagens in the urine, micronuclei in polychromatic erythrocytes, and chromosomal aberrations in metaphase bone marrow cells. Those animals treated by inhalation were also examined for local damage in the lung. The assay for mutagens in the urine was negative as shown by the Ames assay with TA100 and TA98 and there was no increase in micronuclei or in metaphase aberrations. Histological sections from the animals treated by inhalation did not show the presence of particles, macrophage infiltrations and generalized lung damage. We tested the same fly ash with an in vitro cell transformation assay with the cell line Balb/c 3T3 subclone A31-1-13. Although there was not an increase in Type III foci, there was a dose-dependent increase of Type II foci in the treated cells over the controls. In one assay, there was approximately a 14-fold increase in Type II foci in the highest dose (2 mg/ml) compared to the solvent control. One other ash sample induced cell transformation without being markedly cytotoxic, while a third sample was highly toxic but did not induce transformation.

Animals↗
PubMed1989

Aromatic amines and acetamides in Salmonella typhimurium TA98 and TA100: a quantitative structure-activity relation study.

The mutagenicity of a series of 19 aromatic amines had been previously measured in Salmonella typhimurium strains TA98 (frame-shift) and TA100 (base-pair) with the addition of S9 from Aroclor 1254-induced rat liver. A quantitative structure-activity relation (QSAR) study using multiple regression analysis points out the influence of three factors on mutagenicity: lipophilic character, position of the amine group, and whether it is free or acetylated, as expressed by log P and two indicator variables I1 and I2, respectively. The multiple regression equations explain 78 and 88% of the variance in log mutagenicity in TA98 and TA100, respectively. First of all, mutagenicity was shown to increase with lipophilicity. On the other hand, mutagenicity is reduced when the amine or acetamido position is ortho to the juncture because of steric hindrance in its biotransformation compared with a non-ortho isomer. It is decreased also by the acetylation of the amine group, probably because the acetyl group needs to be first split off prior to oxidation of the amine group to -NHOH.

Acetamides↗
PubMed1988

Chromosomal aberrations in the cotton rat, Sigmodon hispidus, exposed to hazardous waste.

The study of chromosome damage in rodents living on hazardous-waste sites may provide evidence of important biological consequences of chronic exposure to toxic chemical wastes. This study compared bone-marrow cells of animals (Sigmodon hispidus) taken from two superfund waste-disposal sites with those from an uncontaminated site and demonstrated that both populations exposed to hazardous wastes had significantly more structural and numerical aberrations than the control population.

Animals↗
PubMed1988

The mutagenicity of urine fractions from patients administered antineoplastic therapy.

A concern among hospital personnel is their exposure to mutagenic drugs and in the incidental exposures that could occur in caring for the patients. In a recent published study the mutagenicity of urine from patients administered antineoplastic drugs was determined and techniques were developed to chemically inactivate the mutagenicity. A question still remained as to what components of the excreted urine were mutagenic. Urine samples from patients receiving mutagenic drugs were fractionated by high pressure liquid chromatography (HPLC) to then assay by the Ames test the collected and concentrated fractions to determine what were the mutagenic compounds in the urine. Urine samples from patients on single agent cancer treatment with cisplatin, cyclophosphamide, doxorubicin and mitomycin C were assayed. In general, all urine samples containing the cytotoxic agents studied were mutagenic because of the presence of the parent compound, except cyclophosphamide which requires activation and therefore an active metabolite was the major mutagenic constituent in the urine sample. This data indicates that the mutagenicity of urine from patients receiving these antineoplastic agents is the result of the parent compound or a single major metabolite.

Antineoplastic Agents↗
PubMed1988

Dinitrochlorobenzene is inherently mutagenic in the presence of trace mutagenic contaminants.

2,4-Dinitrochlorobenzene (DNCB) is used for immunotherapy of alopecia areata and verruca vulgaris. We initially postulated that the presence of mutagenic contaminants in commercially available DNCB might account for part of its mutagenicity. We have now characterized changes in the dose-mutagenic response curve of 99% DNCB modified by adding 1% concentrations of known contaminants: 1-chloro-2-nitrobenzene; 1,3-dinitrobenzene; and 2,4-dichloronitrobenzene. Dose-response curves were generated using Salmonella typhimurium tester strains TA-98 and TA-100 at concentrations of 0, 1, 5, 10, 25, 50, and 100 micrograms per plate in a modified Ames assay. We observed a linear dose-response relationship with a slight, but nonsignificant, shift to the right when contaminants were added. We conclude that DNCB is itself mutagenic, and that contaminants play a minor role in its observed mutagenicity.

Dinitrobenzenes↗
PubMed1987

Stability and inactivation of mutagenic drugs and their metabolites in the urine of patients administered antineoplastic therapy.

Urine samples from patients administered mutagenic antineoplastic drugs are mutagenic in the Ames assay, and hence may pose a genotoxic hazard to hospital personnel or family members caring for the patient. The urine samples in the present study were tested for mutagenicity in several strains of Salmonella typhimurium that were uvr negative (TA98, TA100) or positive (TA102, UTH8413, UTH8414), and were analyzed for the presence of drugs and their metabolites using high-pressure liquid chromatography (HPLC). Urine samples from cancer patients were kept at room temperature and their mutagenicity as well as the chemical stability of the drugs was tested for a period of 14 days. It was observed that, in general, the urine remained mutagenic for the 14-day period while the parent compound degraded within the first seven days. An exception was cisplatin, which was chemically stable as platinum, but the urine decreased in mutagenicity with time. This decrease was probably the result of ligand exchange with the platinum. Inactivation methods were developed to reduce the genotoxic hazard posed by the mutagenic compounds in the urine. Cisplatin was inactivated by complexing with sodium diethyldithiocarbamate (DDTC). Oxidation of urine containing mitomycin C and doxorubicin (sodium thiosulfate must be added to urine containing doxorubicin) with 5.25% sodium hypochlorite solution (bleach) results in mutagenic inactivation. Urine containing cyclophosphamide and its metabolites was oxidized with alkaline potassium permaganate and the active degradation products trapped with sodium thiosulfate. Both chemical and mutagenic assays are necessary to determine the reduction of risk. Methods of inactivation of mutagenic urine developed in this study are both effective and practical for the reduction of exposure to genotoxic hazards.

Antineoplastic Agents↗
PubMed1987

Assessment of diphenylcyclopropenone for photochemically induced mutagenicity in the Ames assay.

The photochemical conversion of diphenylcyclopropenone to diphenylacetylene has recently been reported. Diphenylcyclopropenone is used in the treatment of alopecia areata and is nonmutagenic in a limited Ames assay. We examined diphenylcyclopropenone and diphenylacetylene, as well as synthetic precursors of diphenylcyclopropenone--dibenzylketone and alpha,alpha'-dibromodibenzylketone--for mutagenicity against TA100, TA98, TA102, UTH8413, and UTH8414. All compounds were nonmutagenic except alpha,alpha'-dibromodibenzylketone, which was a potent mutagen in TA100 with and without S-9 activation. The effect of photochemical activation of diphenylcyclopropenone in the presence of bacteria demonstrated mutagenicity in UTH8413 (two times background) at 10 micrograms/plate with S-9 microsomal activation. 8-Methoxypsoralen produces a mutagenic response in TA102 at 0.1 microgram/plate with 60 seconds of exposure to 350 nm light. In vitro photochemically activated Ames assay with S-9 microsomal fraction may enhance the trapping of short-lived photochemically produced high-energy mutagenic intermediates. This technique offers exciting opportunities to trap high-energy intermediates that may play an important role in mutagenesis. This method can be applied to a variety of topically applied dermatologic agents, potentially subjected to photochemical changes in normal use.

Cyclopropanes↗
PubMed1986

Genotoxic evaluation of the offgassing products of particle board.

It has been recognized that people are spending more time indoors and that pollutants are being found in elevated concentrations in this environment. Because the constituents of indoor air pollution can vary relative to a large number of factors, the nature of the indoor environment is extremely difficult to study. Of the materials used in construction of buildings which can elute complex mixtures of organic compounds, products such as particle board, plywood and insulation are known to release formaldehyde into the indoor environment. We have employed a modification of the Ames Salmonella/microsome assay with both DNA repair-proficient and -deficient strains and determined that one such material, particle board, emitted mutagenic and genotoxic substances. The materials offgassing from the particle board demonstrated a dose-related response in both mutagenicity and toxicity. It was also observed that incubation at 37 degrees C produced a decrease in both endpoints which was related to time of incubation. In addition, detectable amounts of twelve other organic compounds were identified as offgassing from the incubated particle board.

Animals↗
PubMed1985

Genotoxic classification of anticancer drugs.

The effects of bacterial DNA excision repair on the mutagenic and lethal actions of 17 injectable anticancer drugs have been used to classify them into three levels of potential risk to medical personnel who are involved in their preparation and administration.

Antineoplastic Agents↗