John G. Babish

A phase I trial of andrographolide in HIV positive patients and normal volunteers.

A phase I dose‐escalating clinical trial of andrographolide from Andrographis paniculata was conducted in 13 HIV positive patients and five HIV uninfected, healthy volunteers. The objectives were primarily to assess safety and tolerability and secondarily to assess effects on plasma virion HIV‐1 RNA levels and CD4+ lymphocyte levels. No subjects used antiretroviral medications during the trial. Those with liver or renal abnormalities were excluded. The planned regimen was 5 mg/kg bodyweight for 3 weeks, escalating to 10 mg/kg bodyweight for 3 weeks, and to 20 mg/kg bodyweight for a final 3 weeks. The trial was interrupted at 6 weeks due to adverse events including an anaphylactic reaction in one patient. All adverse events had resolved by the end of observation. A significant rise in the mean CD4+ lymphocyte level of HIV subjects occurred after administration of 10 mg/kg andrographolide (from a baseline of 405 cells/mm3 to 501 cells/mm3; p = 0.002). There were no statistically significant changes in mean plasma HIV‐1 RNA levels throughout the trial. Andrographolide may inhibit HIV‐induced cell cycle dysregulation, leading to a rise in CD4+ lymphocyte levels in HIV‐1 infected individuals. Copyright

Modification by beet and cabbage diets of aflatoxin B1-induced rat plasma α-foetoprotein elevation, hepatic tumorigenesis, and mutagenicity of urine

Weanling male Fischer rats were fed a purified diet or diets containing 25% (w/w) freeze-dried ground beets or cabbage with or without 1 ppm aflatoxin B1 (AFB1) for 26 wk. In 3-7 wk the cabbage diet diminished, while the beet diet enhanced AFB1-induced plasma alpha-foetoprotein (AFP) elevation. When the experiment was extended to 42 wk by maintaining the animals on the purified (basal) diet for a further 16 wk the rats that had consumed AFB1 in the beet diet had 72 +/- 14 tumours/liver (mean surface diameter of tumours, 6.13 +/0 4.69 mm); animals that had been given AFB1 in the control diet had 30 +/- 16 tumours/liver (mean surface diameter, 4.36 +/- 3.16 mm); rats that had been given AFB1 in the cabbage diet had 13 +/- 5 tumours/liver (mean surface diameter, 4.28 +/- 2.89 mm). In the Salmonella/mammalian microsomal test, urine from rats fed AFB1 with beets caused significantly (P less than 0.05) more revertants in Salmonella typhimurium strain TA98 than did urine from rats fed AFB1 with purified or cabbage diets. The beet- and cabbage-containing diets had no effect on the plasma AFP concentration, hepatic tumorigenesis, or the mutagenicity of urine in rats receiving no AFB1. The evidence suggests that non-nutrient components of common vegetables may influence the response to chemical carcinogens, and that AFP determinations are useful in the rapid identification of dietary factors that modify carcinogenesis.

National survey of elements and other constituents in municipal sewage sludges

Fifty-nine elements, poly chlorinated biphenyls, volatile N-nitrosamines and gamma emission were determined in 30 sewage sludges from 23 American cities using several analytical methods. Relatively high concentrations of toxic metals were found in sludges from specific municipal plants. The pH and levels of calcium and iron in certain of the sludges appeared to reflect the addition of lime, ferric chloride and/or spent pickle liquor during sewage treatment. Of 15 sludges analyzed, the carcinogen, N-nitrosodimethylamine was detected in 14 and various other N-nitrosamines in 12 of them. Based on present federal guidelines, only 7 of the 30 municipal sludges analyzed would be considered suitable for land application owing to their elevated content of one or more heavy metals.

A cell culture analogue of rodent physiology: Application to naphthalene toxicology

The difficulties of large-scale animal testing of compounds has spurred development of in vitro testing methods and physiologically based pharmacokinetic models (PBPK). In existing in vitro methods, tissue interactions occurring in vivo are not reproduced accurately and in PBPKs the a priori prediction of metabolism is difficult. Through development of a multicompartmental, multiple cell type bioreactor system these limitations can be circumvented. A cell culture analogue (CCA) of a PBPK was developed. The CCA contains multiple chambers, each of which represents a tissue or group of similar tissues as specified in the PBPK. Proof-of-concept experiments were done using naphthalene as a model. Naphthalene is converted into naphthalene oxide and the circulation of this reactive metabolite from the liver to lung is a possible mechanism for lung injury. A CCA with liver, lung and other tissue compartments was constructed. This system was used in conjunction with cultured H4IIE rat hepatoma cells and L2 rat lung cells to study the importance of circulated naphthalene metabolites (presumably naphthalene oxides) on lung cell toxicity in rodents. By increasing the number of cells and/or inducing cytochrome P-450 activity in the liver compartment, lung cell mortality was increased. Glutathione depletion in the lung and liver cells was also observed. These results indicate that the CCA is a potentially useful concept for studying the action of compounds with reactive metabolites.

Quercetin: A mutagen, not a carcinogen, in fischer rats

Purified quercetin, as well as diets containing quercetin at 0.1% and 0.2%, are mutagens to Salmonella typhimurium TA100. This mutagenicity is enhanced with the S9 metabolic activation system. The urine of Fischer rats fed the 0.2% quercetin diet also is mutagenic with the S9 activation system, but the feces of these animals exhibited enhanced mutagenicity only without activation. This may indicate different quercetin metabolites in urine and feces. Rats fed these diets for 64 wk showed no consistent tissue lesions, carcinogenicity, or reproductive changes. Male rats fed 0.2% quercetin showed lowered blood serum glutamic oxaloacetic transaminase and urea nitrogen levels, but these values do not reflect pathological changes.

Antibacterial Chemotherapeutants for Finfish Aquaculture: A Synopsis of Laboratory and Field Efficacy and Safety Studies

Abstract This review summarizes the extensive and disparate world literature pertaining to antibacterial chemotherapeutants which may be of use in finfish aquaculture. Currently, the veterinarian or fish health professional in the USA has only two legal antibacterials available, Terramycin for Fish® and Romet-30®, each with limited and specific indications for use including treatable fish species and pathogens. If an indicated bacterial pathogen is not sensitive to these chemotherapeutants, the producer has limited treatment options. Extralabel usage of these or other antibacterials is not permitted via the feed (currently the only practical route for treating large populations of fish) without specific U.S. Food and Drug Administration approval, including the Investigational New Animal Drug (INAD) process or an emergency INAD exemption. Research to develop and approve new antibacterials to treat commercial aquaculture species has identified specific fluoroquinolones (enrofloxacin, sarafloxacin), macrolid...

Health Among Municipal Sewage and Water Treatment Workers

Municipal sewage treatment plant workers are potentially exposed to a multitude of industrial chemicals and pathogenic microorga nisms. A questionnaire survey of working habits, lifestyle and symptoms of illness was conducted among 189 municipal sewage treatment plant workers processing between three and ten million gallons of wastewater daily in 16 plants in New York State between March and July of 1984. Water treatment plant workers in the same cities comprised the comparison group. Sewage workers reported a significantly higher frequency of headache, dizziness, sore throat, skin irritation and diarrhea within the month imme diately preceding receipt of the questionnaire, after controlling for various possible confounders. Eye and skin irritation were signifi cantly associated with exposure to mutagens. The health signifi cance of these findings and possible sources of error in assessing risk are discussed.

Protein tyrosine phosphorylations as an indicator of 2,3,7,8-tetrachloro-p-dioxin exposure in vivo and in vitro

Abstract A dose-dependent increase in tyrosine phosphorylation of five hepatic intracellular proteins with approximate molecular weights of 17, 21, 27, 29, and 34 kDa was seen 24 h after administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to C57BL/6J female mice. The ED 50 values for tyrosylphosphorylation of these five proteins, respectively, were 0.26, 0.21, 0.26, 0.31, and 0.38 μg TCDD/Kg. TCDD induction of 7-ethoxyresorufin O-deethylase activity (EROD) was characterized by an ED 50 of 2.5 μg/Kg. An eighteen h exposure of a human lymphoblastoma cell line (X3) to TCDD increased tyrosylphosphorylation status of ten proteins with approximate molecular weights of 16, 17, 24, 26, 27, 32, 33, 34, 35, and 36 kDa in a dose-dependent manner. The EC 50 values for these TCDD-dependent tyrosylphosphorylation ranged from 0.01 to 0.07 nM TCDD. EROD induction by TCDD in X3 cells exhibited an EC 50 of 0.14 nM. These data indicate that TCDD alters intracellular protein tyrosine phosphorylation and these changes are more sensitive biological indicators of TCDD exposure than induction of EROD.

Noninducibility of cytochrome P-450 in the earthworm Dendrobaena veneta

Cytochrome P-450 has been measured in the earthworm Dendrobaena veneta (Rosa) in a direct spectrophotometric procedure. The P-450 was found not in the dense microsomal fraction, but in the less dense overlying fraction often referred to as buffy coat. Earthworm P-450 was not induced by 3-methylcholanthrene or phenobarbitol.

Toxicologic studies in growing sheep fed silage corn cultured on municipal sludge‐amended acid subsoil

Field corn was grown on subsoil, pH 5.5, that had been amended with 100 dry tons per acre (224 metric tons per hectare) of municipal sewage sludge from Syracuse, New York. The corn plants containing 3.88 ppm dry weight of cadmium were field-chopped and ensiled, and the silage was fed to growing sheep for 225 d. The sheep fed the sludge-grown corn silage showed a significantly (10 higher feed efficiency, (2) higher hepatic microsomal p-nitroanisole O-demethylase activity, and (3) higher concentrations of cadmium in liver and kidney and nickel in kidney as compared to the control animals. No significant treatment effects were observed in mutagenic responses for animal feed or feces samples. No consistent treatment effects were noted during histopathologic examination of sheep tissues.