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R A Becker

Publications and source records attributed to R A Becker.

At least 19 recordsLinked to original sources
PubMed2006

Biomonitoring equivalents: a screening approach for interpreting biomonitoring results from a public health risk perspective.

Advances in both sensitivity and specificity of analytical chemistry have made it possible to quantify substances in human biological specimens, such as blood, urine, and breast milk, in specimen volumes that are practical for collection from individuals. Research laboratories led by the Centers for Disease Control and Prevention (CDC) in its series National Report on Human Exposure to Environmental Chemicals [Centers for Disease Control and Prevention (CDC), 2005. Third National Report on Human Exposure to Environmental Chemicals. NCEH Pub. No. 05-0570.] are dedicating substantial resources to designing and conducting human biomonitoring studies and compiling biomonitoring data for the general population. However, the ability to quantitatively interpret the results of human biomonitoring in the context of a health risk assessment currently lags behind the analytical chemist's ability to make such measurements. The traditional paradigm for human health risk assessment of environmental chemicals involves comparing estimated daily doses to health-based criteria for acceptable, safe, or tolerable daily intakes (for example, reference doses [RfDs], tolerable daily intakes [TDIs], or minimal risk levels [MRLs]) to assess whether estimated doses exceed such health screening levels. However, biomonitoring efforts result in measured chemical concentrations in biological specimens (the result of absorption, distribution, metabolism and excretion of administered doses) rather than estimated intake doses. Quantitative benchmarks of acceptable or safe concentrations in biological specimens (analogous to RfDs, TDIs, or MRLs) needed to interpret these levels exist for very few chemicals of environmental interest. This paper discusses issues inherent in converting existing health screening benchmarks based on intake doses to screening levels for evaluating biomonitoring data, and presents methods and approaches that can be used to derive such screening levels (termed "Biomonitoring Equivalents," or BEs) for a range of chemicals and biological media.

Animals↗
PubMed1995

Isolation of a primate embryonic stem cell line.

Embryonic stem cells have the ability to remain undifferentiated and proliferate indefinitely in vitro while maintaining the potential to differentiate into derivatives of all three embryonic germ layers. Here we report the derivation of a cloned cell line (R278.5) from a rhesus monkey blastocyst that remains undifferentiated in continuous passage for > 1 year, maintains a normal XY karyotype, and expresses the cell surface markers (alkaline phosphatase, stage-specific embryonic antigen 3, stage-specific embryonic antigen 4, TRA-1-60, and TRA-1-81) that are characteristic of human embryonal carcinoma cells. R278.5 cells remain undifferentiated when grown on mouse embryonic fibroblast feeder layers but differentiate or die in the absence of fibroblasts, despite the presence of recombinant human leukemia inhibitory factor. R278.5 cells allowed to differentiate in vitro secrete bioactive chorionic gonadotropin into the medium, express chorionic gonadotropin alpha- and beta-subunit mRNAs, and express alpha-fetoprotein mRNA, indicating trophoblast and endoderm differentiation. When injected into severe combined immunodeficient mice, R278.5 cells consistently differentiate into derivatives of all three embryonic germ layers. These results define R278.5 cells as an embryonic stem cell line, to our knowledge, the first to be derived from any primate species.

Animals↗
PubMed1992

Sister chromatid exchange and chromosome breakage in complete hydatidiform moles.

Women with complete hydatidiform moles (CHM) are at a 10% risk for developing persistent trophoblastic disease or choriocarcinoma. We studied sister chromatid exchange (SCE) as a prognostic indicator for malignancy in peripheral blood lymphocytes (PBL) from women with CHM and their husbands, but found no differences from normal control couples. SCE levels in cultured tissue derived from 11 CHM (avg. 7.9) and 2 choriocarcinomas (avg. 6.8) were not significantly different from those of 8 normal skin fibroblast cultures (avg. 7.8). These same tissues were then examined for chromosome breakage which was significantly higher for CHM (0.48/cell) and choriocarcinoma (0.87/cell) than normal fibroblasts (0.33/cell). Chromosome breaks occurred at 50-60% known fragile sites and at 50-55% of cancer breakpoints. Whereas SCE was only associated with 13% of breaks in the three tissues, half of these were at known fragile sites. Our results suggest that SCE is not an indicator of malignancy in PBL or cultured cells from CHM or choriocarcinoma and that the level of SCE is not elevated in CHM or choriocarcinoma. However, our results confirm the increased breakage seen in the latter two tissues which may represent general DNA instability predisposing to choriocarcinoma and its accompanying chromosomal rearrangements.

Cells, Cultured↗
PubMed1991

Quality of oocytes from superovulated rhesus monkeys.

The parameters, serum oestradiol (E2) response, follicle size and cumulus morphology, which are commonly used to determine in-vivo oocyte maturation in human in-vitro fertilization and embryo transfer (IVF-ET) programmes, were shown to be unreliable predictors of maturation of rhesus oocytes. In two groups of rhesus, one stimulated with pregnant mares' serum gonadotrophin (PMSG) and human chorionic gonadotrophin (HCG) and the other with human menopausal gonadotrophin (HMG) and HCG, the three parameters varied widely within and between protocols. Triple fluorochrome staining (TFS) for chromatin, microtubules and filamentous actin (f-actin) in oocytes at the time of collection and following 24 h in culture showed major differences in their maturation both in vivo and in vitro following priming with PMSG and HMG. In evaluating IVF protocols, TFS provides a valuable assay for the meiotic status of fixed oocytes of non-human primates.

Animals↗
PubMed1987

Alternative methods of selecting rat hepatocellular nodules resistant to 2-acetylaminofluorene.

Dietary 2-acetylaminofluorene (2-AAF) coupled with a stimulus for cell proliferation such as a 2/3 partial hepatectomy (PH) or a necrotizing dose of carbon tetrachloride is frequently employed to generate nodules of resistant ("initiated") rat hepatocytes. This regimen is a useful model for experimental analysis of alterations in hepatocytes during carcinogenesis, and also as an assay for initiation by various carcinogens. Because of the decreasing availability of carcinogen-containing diets from commercial sources, we have developed alternative methods of 2-AAF administration to generate nodules in rats initiated with N-nitrosodiethylamine. This study compared the nodule-selecting and cancer-promoting efficacy of 2-AAF administered by the Solt-Farber procedure (0.02% in diet for 2 weeks) with 2-AAF administered by gavage, as a suspension in 1% aqueous carboxymethyl-cellulose (CMC). Three or 4 daily administrations of 2-AAF by gavage (20 mg/kg/day) followed by PH on day 4 were equivalent to the dietary regimen in generating early resistant nodules, late persistent nodules and hepatocellular carcinomas. These regimens were similar to the dietary regimen of 2-AAF in inhibiting virtually all normal hepatocyte proliferation. These regimens permit control over the duration and level of 2-AAF exposure and the resulting size of selected nodules.

2-Acetylaminofluorene↗
PubMed1987

Ramipril: review of pharmacology.

Ramipril is a potent orally active converting enzyme inhibitor. Its active metabolite ramiprilat is classified as a reversible, slow- and tight-binding inhibitor. Ramipril lowers blood pressure in various models of hypertension and improves states of acute cardiac failure mainly by suppression of angiotensin II formation. Actions on both vasoconstrictor and volume factors are involved because ramipril causes vasodilation and mild natriuresis but preserves potassium. Sustained inhibition of converting enzyme in target tissues such as vascular wall, kidney and heart may explain cardiovascular changes over the long term. Ancillary effects may possibly emerge from modulation of the sympathetic nervous system but the contribution of bradykinin potentiation remains unclear.

Adrenergic Fibers↗
PubMed1987

A summary of the results of 55 chemicals screened for developmental toxicity in mice.

Fifty-five chemicals, including known teratogens, known embryotoxins, equivocal teratogens, nonembryotoxins, and nonteratogens, as well as compounds of unknown teratogenic or embryotoxic potential, were evaluated in the Chernoff/Kavlock developmental toxicity screen. All chemicals were administered by gavage to pregnant ICR/SIM mice on gestation days 8 through 12. The mice were allowed to deliver, and several neonatal growth and viability parameters were measured in the offspring. Comparative statistical analysis of these parameters between treated animals and concurrent (vehicle-treated) controls provided a data base to evaluate the validity of the developmental toxicity screen as an assay to detect teratogens and embryotoxins. Of the 26 compounds reported in the literature to be teratogenic or embryotoxic in mice following oral administration, 24 were positive in the developmental toxicity screen. Of the compounds previously tested in conventional assays and found to be devoid of teratogenic or embryotoxic activity in mice, 93% were negative in the developmental toxicity screen. The importance of experimental design, dose selection, and neonatal growth and viability measurements as they relate to interpretation and evaluation of the results of the developmental toxicity assay are discussed.

Animals↗
PubMed1987

Workshop on the Chernoff/Kavlock preliminary developmental toxicity test.

The Chernoff/Kavlock assay, proposed as a preliminary screen for teratogenic potential, was the subject of a 2-day workshop sponsored by the National Institute for Occupational Safety and Health. Data from three large testing programs were presented, representing tests of 165 chemicals, of which 33 were tested at least twice. Applications of the test in industrial laboratories and product development, hazard identification, and risk assessment were discussed. Workshop participants recognized the assay as one of several valid ways to preliminarily evaluate chemicals with unknown developmental toxicity. Other preliminary tests were also discussed in terms of their relationship to this test, which was seen as having the advantage of providing information on neonatal viability. Other techniques, particularly an abbreviated conventional teratology study, were also recognized as appropriate screens. The preferred test in a particular laboratory will be dependent upon the particular skills and objectives of that laboratory. Standardized protocols were suggested, but flexibility in experimental design was considered necessary, and many variations on the basic test could be appropriate. This preliminary test has been used most often as a single-dose test in mice, but might provide more generally useful data if conducted in rats using two dose levels. Workshop participants viewed the test as highly reliable in correctly identifying developmentally toxic chemicals and suggested that a negative finding in a properly conducted Chernoff/Kavlock test could be a sufficient basis for regulatory agencies to determine that conventional teratology tests in the same species are not warranted.

Animals↗
PubMed1986

Validation of an in vivo developmental toxicity screen in the mouse.

A test system for identifying toxicity, including potential teratogenicity has been developed that is based on growth and viability of embryonic, fetal, and postnatal mice (J Toxicol Environ Health 10:541-550, 1982). To test the utility of this assay, a series of 55 compounds was administered to timed-pregnant ICR/SIM mice during organogenesis. The test compounds included known teratogens, known nonteratogens, and equivocal teratogens. They represented a wide variety of classes including pesticides, organic solvents, metals, steroids, nutrients, food additives, antimetabolites, alkylating agents, and pharmaceutical agents. A single dose level, at or near the level producing overt maternal toxicity in preliminary range-finding studies, was administered by gavage on gestation days 8 through 12. Females were allowed to deliver; litter size and weight on the day of birth and 2 days postpartum were recorded, and stillborns were examined. Dams that had not given birth by gestation days 21 or 22 were killed and their uteri were examined. The results confirmed a strong correlation between reported teratogenic activity and embryo/fetal viability, and/or postnatal growth and viability. The results indicate that this test system is an effective, cost-efficient means of prioritizing compounds for more detailed teratogenicity testing.

Animals↗
PubMed1986

Enhanced O6-methylguanine-DNA alkyltransferase activity in rat liver nodules.

The progression of chemical carcinogen induced hepatic lesions in the rat from altered enzyme foci to hepatocyte nodules and ultimately to hepatocellular carcinoma appears to be related to the evolution of new cell populations within these hepatic lesions. Initiator-promoter-initiator experiments in rat liver models using alkylating agents as the second genotoxic compound suggest accelerated progression toward malignancy could be the result of mutations caused by O6-alkylguanine formation in the DNA of preneoplastic liver cells. Since mutation frequency is believed to be related not only to the extent of O6-alkylguanine formation in DNA, but also to the rate of O6-alkylguanine repair, we measured the activity of the enzyme which repairs O6-alkylguanine, O6-alkylguanine-DNA alkyltransferase, in rat liver nodules. The activity of O6-methylguanine-DNA alkyltransferase in extracts of rat liver nodules 15 and 25 weeks post-initiation was approximately 1.4- and 1.8-fold greater, respectively, than comparable extracts from untreated-control and promoter only-treated rat liver tissues. Thus, the enhanced progression toward malignancy caused by treatment of rats bearing carcinogen-induced preneoplastic hepatic lesions with alkylating agents cannot be explained by a generalized deficiency of O6-alkylguanine-DNA alkyltransferase in hepatic preneoplastic lesions as a whole. These studies show that the distinctive xenobiotic resistant phenotype of rat hepatocyte nodules includes, in addition to the previously documented alterations in xenobiotic activation and detoxification enzyme activities, enhanced activity of a specific DNA repair system.

2-Acetylaminofluorene↗
PubMed1985

Nonthyroidal control of metabolism after burn injury: possible role of glucagon.

The endocrine basis for control of metabolism in nonthyroidal illness is not yet understood. Burn injury is associated with reduced serum concentrations of thyroid hormones and with resting hypermetabolism. One index of severity is total burn size (TBS, % body surface). After overnight fasting and recumbency, resting metabolic rate (MR, O2 consumption) was measured weekly and plasma was sampled for determination of glucose, total cholesterol, triglycerides, insulin, glucagon, somatostatin, growth hormone, norepinephrine, epinephrine, and cortisol in 28 burned men, 17-23 years old, TBS 2%-85%, including 8 controls with minimal injury (TBS less than or equal to 7.5%). MR was elevated in proportion to burn size mainly in the first week then declined toward normal. Growth hormone was not changed. Two multiple regression analyses (validated by random partitioning of data) determined which plasma variables independently reflected residual variation in MR: without TBS entered as a variable, high MR was associated with elevated glucose, cortisol, and glucagon, and low cholesterol (cumulative r2 = 0.79); with TBS entered, high MR was associated with greater TBS, elevated norepinephrine, and again high glucagon and low cholesterol (r2 = 0.81). Resting metabolism after burn injury is controlled not by the thyroid but may be controlled by a set of antiinsulin hormones that does not include growth hormone, but possibly includes glucagon.

Adolescent↗
PubMed1985

DNA ethylation in target and non-target organs of hamsters and rats treated with diethylnitrosamine.

Kinetics of ethylation of target and non-target organ DNA in vivo by diethylnitrosamine (DEN) was compared in rats and Syrian golden hamsters, since published reports indicate a single dose of DEN induces both kidney and liver tumors in rats and almost exclusively respiratory tract tumors in hamsters. Following treatment with 200 mg DEN/kg, 7-ethylguanine (7-etG) was lost more rapidly from hamster than from rat liver DNA, while O6-ethylguanine (O6-etG) persisted longer in hamster than in rat liver DNA. DNA ethylation was not detected in rat lung (non-target organ), while both 7-etG and O6-etG were quantitated in hamster lung (target organ) following DEN treatment. DNA ethylation in rat kidney DNA was approximately 1/10 of that in liver by 200 mg DEN/kg, and the persistence of 7-etG and O6-etG differed only slightly in these tissues. Ethylation of hamster liver DNA by DEN at doses between 20 and 200 mg/kg, as measured by 7-etG and O6-etG was proportional to the dose of carcinogen up to 160 mg/kg; at larger doses DNA ethylation sharply increased. Differences in the persistence of O6-etG between DEN-treated rats and hamsters cannot solely account for species differences in the organotropism of DEN carcinogenesis.

Alkylation↗
PubMed1985

Repair of O4-methyldeoxythymidine residues in DNA by mammalian liver extracts.

The enzymatic repair of O4-methyldeoxythymidine (O4-MedT) by mammalian liver extracts was investigated in vitro using double-stranded poly[d(A-T) X d(A-T)] alkylated with N-[methyl-3H]-N-nitrosourea as a substrate. The removal of O4-MedT by monkey liver extracts was proportional to the protein concentration of the reaction mixture up to approximately 4 mg/ml, while kinetic analysis revealed the repair reaction reached a plateau by 2 h at 37 degrees C. The removal of O4-MedT could not be accounted for by contaminating nuclease activity, for greater than 90% of the 3-methyldeoxythymidine (3-MedT) was always recovered, whereas O4-MedT declined to as little as 25% of control values. A DNA-glycoslyase is not involved in the repair of O4-MedT, for O4-methylthymine, the free base, was not detected in supernatants from monkey liver reaction mixtures following incubation with substrate and precipitation of macromolecules with ethanol, even though analysis of nucleic acid digests of these assays revealed O4-MedT was lost from the substrate. The order of O4MedT repair activity in human, monkey, partially hepatectomized rat and methylguanine DNA-methyltransferase activity, with human and monkey most active, partially hepatectomized rat intermediate in activity and control rat least active. Our findings suggest the same, or a similarly regulated mammalian liver DNA-methyltransferase repairs O6-methylguanine and O4-MedT residues in DNA, yet the affinity of the enzyme(s) differs for these promutagenic adducts, as we estimate 30-50 O6-methylguanines would be repaired for every one O4-MedT repaired.

Animals↗
PubMed1985

Kinetics of formation and persistence of ethylguanines in DNA of rats and hamsters treated with diethylnitrosamine.

The kinetics of formation and persistence of 7-ethylguanine (e7Gua) and O6-ethylguanine (O6eGua) were determined in rat liver and kidney DNA following i.p. injection with 12.5, 50, 100, or 200 mg DENA per kg body weight. The rate of ethylguanine formation in hepatic DNA was independent of carcinogen dose; however, the maximum level of DNA ethylation reached was linearly related to DENA dose. Persistence of O6eGua but not e7Gua in rat liver DNA appeared to be dose-dependent; the rate of decline in O6eGua concentration slowed as the dose of DENA increased. Ethylation of rat kidney DNA was quantifiable only following treatment with 200 mg DENA per kg body weight, and maximum concentrations of e7Gua and O6eGua were approximately ten times less than those in hepatic DNA of these animals. Nevertheless, elimination of e7Gua and O6eGua from DNA occurred at similar rates in these tissues. Whereas lung DNA from DENA-treated rats contained no detectable ethylguanines, both e7Gua and O6eGua were detected in lung DNA from treated hamsters. The half-life of e7Gua in hamster lung DNA was 28 h, while O6eGua persisted longer, exhibiting a half-life of 91 h. Only trace quantities of e7Gua and O6eGua were detected in hamster kidney DNA, precluding an accurate estimation of the kinetics of DNA alkylation in this tissue. The rate of formation of ethylguanines in hepatic DNA was faster in hamster than in rat, while maximum levels of e7Gua and O6eGua were similar in these two species. Persistence of both e7Gua and O6eGua was markedly different in hepatic DNA of rats and hamsters. e7Gua was eliminated at a faster rate in the hamster (half-life of 20 h), as compared to the rat (half-life of 35 h). Conversely, O6eGua persisted longer in hamster than in rat liver DNA; a half-life of 34 h was found for the hamster, compared to a half-life of 14 h for the rat. The half-lives of e7Gua and O6eGua in hepatic DNA of DENA-treated rats and hamsters were similar to those reported previously for m7Gua and O6mGua in these species, suggesting that the same enzymatic DNA repair systems act upon these structurally related DNA adducts. The formation and prolonged persistence of O6eGua in lung DNA of DENA-treated hamsters may be related to the sensitivity of this species to the induction of respiratory tract neoplasms following exposure to DENA.

Alkylation↗
PubMed1984

Toxoplasmosis presenting as panhypopituitarism in a patient with the acquired immune deficiency syndrome.

A 57-year-old man with a prior episode of lymphatic toxoplasmosis presented with signs of anterior panhypopituitarism, which was confirmed by standard endocrinologic evaluation. The diagnosis of central nervous system toxoplasmosis was established by brain biopsy after nondiagnostic serologic and radiographic studies. At autopsy, the anterior pituitary was necrotic, with Toxoplasma abscesses in neighboring brain structures. Clinical and laboratory data met the criteria for the acquired immune deficiency syndrome. Although this is the first reported case of toxoplasmosis presenting as panhypopituitarism, future cases may be identified since central nervous system toxoplasmosis is being recognized more frequently in patients with immunodeficiency.

Acquired Immunodeficiency Syndrome↗
PubMed1984

Opioid and dopamine involvement in prolactin release induced by arginine vasotocin and vasopressin in the male rat.

The potential involvement of the endogenous opioid and dopamine (DA) systems in the mechanism(s) mediating arginine vasotocin (AVT)- and arginine vasopressin (AVP)-induced prolactin (PRL) release was investigated in vivo. The injection of AVT (5 micrograms) into unanesthetized male rats resulted in a 2-fold stimulation of PRL release 15 min later, followed by an inhibition of PRL release 30 min thereafter; both the stimulatory and inhibitory PRL responses to AVT were obviated by naloxone (NAL) (200 micrograms). Similarly, the administration of either AVT or AVP (5 micrograms) to urethane-anesthetized rats led to a 3- and 5-fold increase in plasma PRL levels, respectively, 10 min after injection. The PRL stimulatory response to both peptides was completely blocked by pretreating the animals with apomorphine (APO) (5 mg); however, the injection of APO by itself had no effect on PRL secretion in these animals. Both AVT and AVP were also effective in stimulating PRL release 10 min after injection in estrogen (50 micrograms)-progesterone (25 mg) (EP)-treated rats anesthetized with urethane. APO negated the PRL stimulatory response to these compounds in the EP-treated rat as well. Normal, urethane-treated rats experienced a 7- to 8-fold increase in PRL levels 20 min following the injection of methysergide (MET) (250 micrograms). Both AVT and AVP caused approximately a 2.5-fold greater PRL response in MET-treated animals than in AVT and AVP controls, respectively; however, only in the MET + AVT-treated rats was the PRL stimulatory response greater than in the MET controls. MET probably stimulated PRL through its DA antagonistic properties.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗