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Biomedical subjects

R E Albert

Publications and source records attributed to R E Albert.

At least 37 records · Page 2Linked to original sources
PubMed1989

Carcinogen risk assessment.

A molecular biological rationale for the linear nonthreshold dose-response pattern for carcinogenesis is presented based on the mutagenic activation of oncogens as the basis of initiation. The approach assumes that the linear nonthreshold dose pattern at very low doses applies only to tissues that are promoted by intrinsic and extrinsic agents other than the one being modeled, and that risk is characterized on a relative rather than absolute basis in terms of aggregate tumor response.

Animals↗
PubMed1989

Multiple stages in radiation carcinogenesis of rat skin.

Epithelial cell cancers are induced in rat skin by ionizing radiation in a manner that is consistent with the dual action (i.e., two alterations) hypothesis of radiation effects on DNA. This hypothesis states simply that two initial alterations, presumably in the DNA, are necessary to start a normal cell on the pathway to cancer. The initial radiation-induced alteration in the DNA is repairable as indicated by the reduction in tumor incidence with increasing time between dose fractions; the repair halftime is estimated to be 3.0 +/- 1.0 hr. Theoretical predictions of a specific dependence of tumor incidence on linear energy transfer (LET) have been verified experimentally for two specific LET values. However, the theoretical formulation provides no guidance regarding the observed reduction in the carcinogenic action of radiation with age at the time of exposure. Analysis of the tumor DNA for oncogene activation indicated k-ras and c-myc oncogenes were activated in highly anaplastic rat skin cancers, whereas only one of these oncogenes, usually c-myc, was activated in comparatively benign basal cell carcinomas and in squamous cell carcinomas.

Aging↗
PubMed1988

The carcinogenicity of discontinuous inhaled benzene exposures in CD-1 and C57Bl/6 mice.

Groups of male C57Bl and CD-1 mice were exposed to benzene via inhalation using two different exposure protocols. One protocol consisted of repetitive week-long exposures to 300 ppm benzene (6 h/d x 5 d/wk) interrupted by 2 weeks of non-exposure. The exposure pattern (1 week of exposure followed by 2 weeks of non-exposure) was continued until the death of the last exposed animal. The second protocol consisted of exposures to 1200 ppm benzene (6 h/d x 5 d/wk) for 10 weeks. Exposures were then terminated and the animals allowed to live out their lives. For each protocol, appropriate age-matched control mice received comparable exposures to filtered, conditioned air. The discontinuous exposure patterns mimic the patterns of exposure often encountered in the workplace and, in addition, prolong the survival of exposed animals so as to maximize potential tumorigenic responses. Both exposure protocols were markedly hematotoxic to both mouse strains as measured by peripheral blood counts. Both strains of mice responded to the intermittent 300 ppm benzene exposures with elevated incidences of malignant tumors. Particularly noteworthy was a 35% incidence of zymbal gland tumors in the C57Bl mice. In contrast, only the CD-1 mice responded to the 1200 ppm benzene exposures delivered over 10 weeks with elevated tumor incidences. A 46% incidence of lung adenoma was particularly striking in these mice. Neither of the benzene exposure protocols induced elevated incidences of leukemia/lymphoma in either strain.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗
PubMed1987

Inhalation carcinogenesis of various alkylating agents.

A series of earlier studies showed that inhalation exposures of rats to three water-reactive electrophilic compounds produced brisk yields of nasal cancer even when the animals were exposed for only 30 days (6 hr/day X 5 day/wk). In addition, carcinogenic potencies of the compounds appeared to relate to their chemical reactivities as measured by hydrolysis rates. For a further study of this phenomenon, inhalation exposures were conducted with five additional water-reactive compounds: beta-propiolactone [(BPL) CAS: 57-57-8], methylmethane sulfonate [(MMS) CAS: 66-27-3], ethylchloroformate [(ECF) CAS: 541-41-3], dichloroacetyl chloride [(DCAC) CAS: 79-36-7], and propylene oxide [(PO) CAS: 75-56-9] on male Sprague-Dawley rats. The hydrolysis rates of these compounds span 6 orders of magnitude. The compounds were administered for 30 days (6 hr/day X 5 days/wk) with the use of exposure concentrations that were inversely proportional to the respective hydrolysis rates. With this protocol, all compounds except PO (the slowest reacting compound) produced nasal cancer in rats. The concentrations of MMS and BPL employed in the studies produced similar nasal cancer yields, indicating that the carcinogenic potencies of these compounds in rat nasal mucosa were proportional to their hydrolysis rates. The nasal cancer yields of DCAC and ECF were less than expected. DCAC hydrolyzes so rapidly at in vivo temperatures (half-life much less than 0.01 min) that it may not reach target DNA in reactive form. Why the exposures to ECF produced yields of nasal cancer not predicted by its reactivity is currently under investigation. These results combined with our earlier results demonstrate that the carcinogenic potencies of some inhaled reactive electrophilic compounds are related to their hydrolysis rates.

Acetates↗
PubMed1986

Airborne particles, their use in the respiratory system to measure air flow, function, and clearance.

Nonhygroscopic monodisperse particles can be used to estimate airway dimensions within chosen regions of the respiratory tract. These dimensions correspond well with those measured in inflation-fixed lungs. The dispersion of a bolus of airborne particles on inhalation and exhalation is very sensitive to the dimensions of the airways through which the bolus passes, yielding indices of dispersion that provide sensitive indicators of changes in airway dimensions, eg, with smoking. The rates of clearance of particles from the lungs are determined using gamma-labelled particles whose lung retention is determined by external measurements. There are major differences between the deep lung and the ciliated airways. Changes in clearance rates are caused by disease or inhaled intoxicants such as cigarette smoke. At lower levels of irritant exposure, an acceleration of clearance rate is observed, while higher doses and longer periods of exposure produce decreased rates. It is suggested that aerosol techniques may have useful clinical applications; approaches are suggested for such applications.

Adult↗
PubMed1986

The time to tumor approach in risk assessment.

The multistage model is currently a widely used mathematical tool in carcinogen risk assessment to obtain a low-dose linear non-threshold slope for estimating cancer risks and comparing carcinogens with respect to potency. However, the multistage model is a single pathway model, whereas biological evidence indicates that carcinogenesis proceeds through multiple pathways. Furthermore, recent studies suggest that carcinogens induce a generalized increase in the susceptibility to neoplastic transformation triggered as rare events by cell proliferation. Such evidence supports the dtn = c time to tumor model in a modified form.

Carcinogens↗
PubMed1986

Relationships between the levels of binding to DNA and the carcinogenic potencies in rat nasal mucosa for three alkylating agents.

Three direct-acting carcinogens, beta-propiolactone (BPL), methylmethane sulfonate (MMS), and dimethylcarbamyl chloride (DMCC), were evaluated for their carcinogenic potencies in the nasal mucosa of rats and for their abilities to bind in vivo to rat nasal mucosal DNA. The relative carcinogenic potencies of BPL and MMS corresponded well with their overall levels of binding to nasal mucosal DNA. DMCC, however, the most potent carcinogen of the three compounds, produced the lowest level of binding to nasal mucosal DNA. These results indicate that the DNA adducts formed by DMCC in rat nasal mucosa DNA are more readily expressed as cancer than those formed by BPL or MMS.

Alkylating Agents↗
PubMed1986

Contribution of formaldehyde to respiratory cancer.

This article reviews the available data on the carcinogenicity of formaldehyde from experimental and epidemiologic studies and makes recommendations for further research. Two definitive chronic inhalation bioassays on rodents have demonstrated that formaldehyde produces nasal cancer in rats and mice at 14 ppm and in rats at 6 ppm, which is within the domain of present permissible human exposure (8-hr time-weighted average of 3 ppm, a 5 ppm ceiling, and a 10 ppm short-term exposure limit). Biochemical and physiologic studies in rats have shown that inhaled formaldehyde can depress respiration, inhibit mucociliary clearance, stimulate cell proliferation, and crosslink DNA and protein in the nasal mucosa. No deaths from nasal cancer have been reported in epidemiologic studies of cohorts exposed to formaldehyde, but three case-control studies suggest the possibility of increased risk. Although excesses of lung cancer deaths have been observed in some studies at industrial plants with formaldehyde exposure, uncertainties in interpretation limit the evaluation of these findings. Excess cancers of the brain and of lymphatic and hematopoietic tissues have been reported in certain studies of industrial groups and in most studies of formaldehyde-exposed professionals, but whether these excesses are related to formaldehyde exposure is not known. Several properties of formaldehyde pose unique problems for future research: the mechanisms responsible for its nonlinear response; its probable mechanism of carcinogenic action as a cross-linking agent; its formation in tissues as a normal metabolite; its possible action as a promoter and/or a cocarcinogen; and the importance of glutathione as a host defense at low exposure.

Air Pollutants↗
PubMed1986

Rapid induction of thymic lymphomas by isopropyl methanesulfonate: a preliminary report.

The direct-acting SN1 alkylating agent isopropyl methanesulfonate (IMS) was carcinogenic by subcutaneous injection in female Hsd:(ICR)BR mice, causing thymic lymphoid neoplasms within 7 months in at least 20 of 32 treated mice. No such neoplasms were observed in mice treated with the direct-acting SN2 methyl homolog, methyl methanesulfonate (MMS). Both the IMS-treated mice and the MMS-treated mice initially received 20 mumole of the respective compounds by sc injection once weekly; however, because of toxic effects the dose of IMS was reduced to 10 mumole per injection on the 63rd day and further reduced to 5 mumole per injection on the 120th day, after which this dose was maintained until the 202nd day when the last surviving IMS-treated mouse became moribund and was sacrificed. In 2 of the MMS-treated mice, 93% of which were alive at 288 days, tumors were observed at the site of injection, one being a papilloma and the other a subcutaneous sarcoma. IMS has not previously been implicated as a carcinogen, to our knowledge. Its induction of thymic lymphomas may conceivably be related to its ability to alkylate exocyclic oxygen atoms in the DNA of hemopoietic cells.

Animals↗
PubMed1985

Effects of submicrometer sulfuric acid aerosols on mucociliary transport and respiratory mechanics in asymptomatic asthmatics.

The effects of a 1-hr inhalation of submicrometer sulfuric acid (H2SO4) aerosols via nasal mask on tracheobronchial mucociliary particle clearance and respiratory mechanics were studied in ten subjects with asthmatic histories. A brief inhalation of monodisperse 3.9-micron 99mTc-tagged Fe2O3 aerosol preceded the 1-hr H2SO4 (at 100, 300, and 1000 micrograms/m3) or a sham exposure. Thoracic retention of the gamma-tagged Fe2O3 was measured using external radiation detectors. Respiratory function was measured before, and 15 min and 3 hr after the H2SO4 or sham exposure. After exposure to 1000 micrograms/m3 of H2SO4, the six subjects not on routine medication exhibited a transient slowing of mucociliary clearance and also decrements in sGaw, FEV1/FVC, MMEF, and V25 (P less than 0.05) in both sets of measurements. The four asthmatics on daily medication exhibited stepwise mucociliary clearance that was too variable to allow detection of any H2SO4 effect on clearance. The 1000 micrograms/m3 of H2SO4 did produce decrements in V25 (P less than 0.05), but the variability of the other respiratory parameters in this small group was too great to permit detection of changes. Mucociliary clearance rates in both groups in the sham exposure tests were significantly slower than those of healthy nonsmokers studied previously using the same protocols. The extent of mucociliary clearance slowing following the 1000 micrograms/m3 exposure in the nonmedicated subjects was similar to that in the healthy nonsmokers. This similar change, from a reduced baseline rate of clearance, together with the significant change in respiratory function, indicate that asymptomatic asthmatics may respond to H2SO4 exposures with functional changes of greater potential health significance than do healthy nonsmokers.

Adult↗
PubMed1985

Carcinogenicity of formaldehyde and hydrogen chloride in rats.

Previous studies in this laboratory have shown that the combined exposure of hydrogen chloride (HCI) and formaldehyde vapors (HCHO) elicited a significant incidence of nasal cancer in rats. In studies performed elsewhere, it has been demonstrated that exposure to formaldehyde alone induced a high nasal cancer response in rats. We wished to determine whether concurrent exposure of hydrogen chloride would enhance the tumorigenic effects of formaldehyde. Two exposure techniques were used. In one hydrogen chloride and formaldehyde were premixed at high concentrations before entry into the exposure chambers in order to maximize the formation of reactive alkylating agents. In the second the hydrogen chloride and formaldehyde were introduced separately into the exposure chamber. Appropriate control exposures consisting of formaldehyde alone or hydrogen chloride alone or air alone were also performed. The results show that nasal cancer incidences were induced in all animals receiving HCHO regardless of concurrent exposure to hydrogen chloride. The tumors were predominantly squamous cell type arising from the anterior portion of the nasal cavity. This study demonstrates that hydrogen chloride does not appreciably influence the nasal carcinogenicity of formaldehyde.

Animals↗
PubMed1985

Carcinogen specificity in the activation of transforming genes by direct-acting alkylating agents.

DNAs from rat nasal and mouse skin carcinomas and fibrosarcomas induced by the alkylating agents methylmethane sulfonate (MMS), beta-propiolactone (BPL), and dimethylcarbamyl chloride (DMCC) were tested for their ability to transform NIH3T3 cells by DNA transfection. Each of eight MMS-induced rat nasal carcinomas and two of five BPL-induced mouse skin tumors were positive in the transfection assay while all of four fibrosarcomas and six carcinomas induced by DMCC were negative. Anchorage independent growth, tumorigenicity in nude mice, and secondary transfection confirmed the transformed phenotype of the positive transfectants. The transfectants from MMS-induced tumor DNAs did not contain restriction fragments homologous to rat H-, K- or N-ras oncogenes although exogenous (rat) tumor-derived DNA sequences were detected in transfectant genomes by Southern analysis. In contrast a BPL-induced mouse skin tumor showed evidence of containing activated H-ras. These results suggest specificity among causal chemical carcinogens for activation of transforming genes in experimental tumors.

Alkylating Agents↗