Journal of Toxicology and Environmental Health

Krogh, Palle; Gyrd‐Hansen, Nils; Hald, Benedicte; Larsen, Steen; Nielsen, Jens Peter; Smith, Mogens; Ivanoff, Chris; Meisner, Herman

doi: 10.1080/15287398809531092pmid: 2891856

Enzyme activities have been measured in needle biopsies from kidneys of pigs fed 1 ppm or 0.2 ppm of ochratoxin A for 1–5 wks. After feeding 1 ppm toxin for 1 wk, the activity of cytosolic phosphoenolpyruvate carboxykinase (PEPCK) was decreased by 40% and remained inhibited until the termination of the experiment (5 wk). The activity of gamma‐glutamyl transpeptidase, a brush‐border enzyme found in the proximal tubules, was reduced to a similar degree and remained inhibited. The activities of hexokinase, a cytosolic enzyme of general distribution in the nephron, and phosphate‐dependent glutaminase, a distal tubule enzyme, were not affected. The biopsy results were confirmed by measurements in renal slices taken at the termination of the experiment, except that biopsy samples showed more variation in enzyme activity and a lower PEPCK activity. A guinea pig antibody against the cytosolic form of PEPCK was used to demonstrate that the mitochondrial form of the enzyme, which accounts for a considerable part of the total cellular activity, was not affected by ochratoxin A. When mitochondrial PEPCK activity present in the cytosolic fraction was accounted for, ochratoxin A was found to reduce PEPCK activity by 70–80%. The increase of ochratoxin A exposure from zero through 0.2 ppm to 1 ppm, which resulted in dose‐dependent activity decrease of PEPCK and gamma‐glutamyl transpeptidase, was accompanied by dose‐dependent decrease of renal function, as measured by a reduction of maximal tubular excretion of para‐aminohippurate per clearance of inulin (TmPAH/Cln) and an increase in glucose excretion. This suggest that these enzymes are sensitive indicators of ochratoxin A‐induced porcine nephropathy. Assuming that porcine nephropathy represents a valid model of endemic (Balkan) nephropathy in humans, the measurement of cytosolic PEPCK and gamma‐glutamyl transpeptidase activity in the kidney could be a sensitive test for ochratoxin A‐induced disease in humans.

Walaszek, Z.; Hanausek‐Walaszek, M.; Webb, T. E.

doi: 10.1080/15287398809531093pmid: 3336058

The degree of induction of an oncofetal protein marker in rodents by selected chemical carcinogens has been correlated with changes in carcinogenicity induced by dietary D‐glucaro‐1,4‐lactone (GL) based anticarcinogens. These potent anticarcinogens may act to increase the clearance of carcinogens as glucuronides through the inhibition of β‐glucuronidase. The sustained‐release forms are particularly effective, 7.5 mmol/kg of GL maintaining serum β‐glucuronidase activity at or below 50% for only 1 h, while an equivalent amount of calcium glucarate (CCT) maintained this level of inhibition for over 5 h. CCT or other sustained‐release inhibitors, when fed to rodents during administration of carcinogens that undergo glucuronidation, caused a marked reduction in the induction of the marker protein. For those systems where other markers of carcinogenesis were also assessed, it was determined that the inhibition of marker‐protein induction was quantitatively similar to both the inhibition of binding of the carcinogen to DNA and the subsequent induction of tumors in target organs.

Paustenbach, Dennis J.

doi: 10.1080/15287398809531094pmid: 3275786

This risk assessment evaluates the potential human hazards of adverse developmental effects posed by exposure to 2‐ethoxyethanol (2‐EE), 2‐ethoxyethanol acetate (2‐EEA), 2‐methoxyethanol (2‐ME), and 2‐methoxyethanol acetate (2‐MEA) as they are currently used in semiconductor manufacturing. These glycol ethers are contained in positive photoresists used in the wafer fabrication process. The available data on the developmental toxicology of these glycol ethers indicates that each can selectively affect the offspring of pregnant animals that have been exposed to relatively low vapor concentrations. For these chemicals, the ratio of the lowest dose which adversely affected the pregnant animals (A) and the lowest dose which produced developmental effects in offspring (D), e.g., A/D ranged from 1–5. Approximately 400 workplace air samples of 4–8 h duration, both personal and area, from seven different companies were used to assess the degree of inhalation exposure during the manufacture of wafers. The geometric mean results obtained during personal sampling of workplace air for 2‐EE, 2‐EEA, 2‐ME, and 2‐MEA were 0.36, 0.02, 0.10, and 0.01 ppm, respectively. These levels are 14‐ to 500‐fold lower than the applicable threshold limit value (TLV) currently recommended by the American Conference of Governmental Industrial Hygienists (ACCIH). Specifically, the margins of safety between the typical occupational exposure and the TLV for 2‐ME, 2‐EE, 2‐MEA, and 2‐EEA are 50,14, 500, and 250, respectively. The TLVs for these chemicals were set at levels considered sufficiently low to protect workers and their offspring from adverse effects and are about 2‐ to 10‐fold lower than the various no‐observed‐effect levels (NOELs) obtained in animal tests. Based on more recent data, lower TLVs are indicated. The safety‐factor approach, rather than mathematical models developed for estimating cancer risks, was used in this analysis. Historical data have shown that the application of safety factors of 10–100 to the NOEL, as determined in Segment II developmental toxicology tests in animals, should be adequate to protect humans. In its risk assessment guidelines, the U.S. Environmental Protection Agency (EPA) selected the uncertainty‐factor approach as the most reasonable one for evaluating the hazards of developmental toxicants. This assessment indicates that the airborne concentrations of these glycol ethers in the semiconductor industry are, in general, sufficiently low to protect employees against their adverse developmental and reproductive effects as well as any other toxic effects as long as dermal exposure is minimal.

Basinger, Mark A.; Jones, Mark M.; Holscher, Myron A.; Vaughn, William K.

doi: 10.1080/15287398809531095pmid: 2826797

An examination has been carried out on the relative efficacy of a number of chelating agents when acting as antagonists for oral cadmium chloride intoxication in mice. The compounds were administered orally after the oral administration of cadmium chloride at 1 mmol/kg. Of the compounds examined, several were useful in terms of enhancing survival, but by far the most effective in both enhancing survival and leaving minimal residual levels of cadmium in the liver and the kidney, was meso‐2,3‐dimercaptosuccinic acid (DMSA). Several polyaminocarboxylic acids also enhanced survival. The most effective of these in reducing liver and kidney levels of cadmium were diethylenetriaminepentaacetic acid (DTPA), trans‐1,2‐diaminocyclohexane‐N,N,N'N'‐tetraacetic acid (CDTA), and triethylenetetraminehexaacetic acid (TTHA). D‐Penicillamine (DPA) was found to promote survival but also led to kidney cadmium levels higher than those found in the controls. Sodium 2,3‐dimercaptopropane‐1‐sulfonate (DMPS) was as effective in promoting survival as DMSA but left levels of cadmium in the kidney and liver that were approximately four times greater than those found with DMSA.

Jones, Shirley G.; Jones, Mark M.; Holscher, Myron A.; Vaughn, William K.

doi: 10.1080/15287398809531096pmid: 3336059

In comparison with similar experiments in which no zinc acetate was used, the addition of small amounts of zinc acetate to sodium N‐methyl‐N‐dithiocarboxyglucamine produces a significant increase in the amount of cadmium mobilized from the liver and kidneys of mice loaded ip with 10 mg CdCl2·2.5H2O/kg 2 wk prior to the initiation of treatment. Neither treatment results in the transport of significant amounts of cadmium to the brain. The injection of zinc acetate alone did not produce this effect. Experiments in which zinc acetate in drinking water was administered to cadmium‐loaded animals showed that the liver and kidney cadmium levels were significantly increased, presumably via zinc‐mediated processes in which cadmium from other organs was mobilized to the liver and kidneys.

Wilson, Barry W.; Henderson, John D.; Chow, Edward; Schreider, Jay; Goldman, Marvin; Culbertson, Roger; Dacre, Jack C.

doi: 10.1080/15287398809531097pmid: 3336055

The neurotoxicities of single doses of a chemical warfare agent VX lphosphonothioic acid, methyl‐S‐(2‐lbis(1‐methylethyl)amino]ethyl) O‐ethyl ester], a metabolite of the agricultural chemical parathion, paraoxon, PO (phosphonothioic acid, diethyl paranitrophenyl ester), and the known neuropathic agents DFP] phosphorofluoridic acid, bis(l‐methylethyl) ester] and TOCP (phosphoric acid, tri‐o‐tolyl ester) were compared in the chicken. Single injections (subcutaneous, sc) of VX as high as 150 μg/kg (5 times the LD50, intramuscular, im) were tolerated by laying tens if atropine and 2‐pralidoxime were used as antidotes before and immediately after injection. The 150 of VX for inhibition of chicken brain acetylcholinesterase was approximately 5 × 10‐10. Plasma acetylcholinesterase, but not butyrylcholinesterase, was depressed 2 h after injections of 2–20 μg VX/kg im without antidotes. Levels of plasma enzymes such as creatine kinase, indicative of tissue damage, were increased after exposure to both VX and PO. Injections of up to 150 μg/kg of VX with antidotes did not cause locomotor or histological signs of organophosphorus‐induced delayed neuropathy, but single injections of 400 mg TOCP/kg did.

Wilson, Barry W.; Henderson, John D.; Kellner, Thomas P.; Goldman, Marvin; Higgins, Robert J.; Dacre, Jack C.

doi: 10.1080/15287398809531098pmid: 3336056

Hens were repeatedly exposed to paraoxon (PO, phosphonothioic acid, diethyl paranitrophenyl ester), the chemical warfare agent VX [phosphorofluoridic acid, methyl‐S‐(2‐[bis(1‐methylethyl)amino]ethyl)O‐ethyl ester], or the neuropathic DFP [phosphorofluoridic acid, bis(1‐methylethyl)ester] as evidence was sought for nerve or other tissue damage following long‐term treatments at high dose levels. Thirty‐day and 90‐d trials were performed in which each bird was injected 3 or 5 times per week with atropine as protection, weighed, their eggs collected, and their blood enzymes (cholinesterases creatine kinase, and lactic dehydrogenase) and locomotion periodically examined. Muscle and brain enzymes were assayed at the end of the experiments. Doses of PO and VX were at or above LD50 levels. DFP doses were lowered with each run to estimate a no‐observable‐effect level for organophosphate‐induced delayed‐neuropathy (OPIDN). No abnormalities attributable to repeated exposures to either PO or VX were found, even though acute, short‐term symptoms of toxicity appeared after each injection. No evidence for OPIDN was obtained with repeated exposures to PO and VX under conditions where OPIDN was caused by DFP. Histological signs of OPIDN appeared in the spinal cord without gross symptoms of ataxia following repeated treatments of 25 mg/kg of DFP. The results of one experiment suggested that exposure to protective injections of atropine delays the appearance of the locomotor symptoms of the DFP‐induced neuropathy.

Ganey, Patricia E.; Roth, Robert A.

doi: 10.1080/15287398809531099pmid: 3336057

Monocrotaline pyrrole (MCTP) causes pulmonary vascular injury and pulmonary hypertension in rats. Although the mechanism by which MCTP causes pulmonary hypertension is unknown, vasoconstriction may play a role. Thromboxane (Tx) A2 is a vasoconstrictor released from platelets and other blood cells. Following treatment with MCTP in vivo, the release of stable metabolites of TxA2 and prostacyclin [TxB2 and 6‐keto prostaglandin F1α (6‐keto‐PGF1α), respectively] was determined in isolated lungs perfused with blood. Early in the development of pulmonary hypertension, the concentrations of TxB2 and 6‐keto‐PCF1α in the effluent plasma of lungs from treated rats were not different from control rats. When pulmonary hypertension was well established, the concentration of TxB2 was higher in the effluent plasma of lungs from MCTP‐treated rats, although the concentration of 6‐keto‐PCF1α was not affected by treatment.

Neri, L. C.; Kehrer, P.; Woolley, Dorothy E.; Puxty, John

doi: 10.1080/15287398809531100pmid: N/A

ENVIRONMENTAL EPIDEMIOLOGY. Proceedings of the Symposium on Exposure Measurement and Evaluation Methods for Epidemiology, presented at the 190th Meeting of the American Chemical Society, held in Chicago, September 1985. Edited by Fred Kopfler and Gunther Graun, Lewis Publishers, Chelsea, Michigan, 1986, 284 pp., $49.95. A TEXTBOOK OF MODERN TOXICOLOGY. E. Hodgson and P. E. Levi, Elsevier, New York, 1987, 386 pp., $39.50. NEUROPHARMACOLOGY AND PESTICIDE ACTION. Based on symposium Neurotox ‘85, held at University of Bath, England. Edited by M. G. Ford, G. G. Lunt, R. C. Reay, and P. R. N. Usherwood. VCH Publishers, Deerfield Beach, Florida, 1986, 512 pp., $124.00. ENVIRONMENTAL TOXICITY AND THE AGING PROCESSES. Proceedings of a Workshop held in Columbia, Maryland, October 1985. Edited by Scott R. Baker and Marvin Rogul. Alan R. Liss, New York, 1987, 139 pp., $39.50.