Examining the risks and benefits of considering both the traditional dose--response and hormesis in arriving at an acceptable exposure level.

In examining traditional dose-response and hormesis, we have considered the case examples of pulmonary hyperplasia following inhalation of carbon black and pulmonary hyperplasia after methyleneindolenine (3MEIN) exposures, development of irreversible pulmonary fibrosis, effect of continuous exercise and low-level lead exposures, and colorectal cancer. Adaptation can be used to estimate conventional dose responses. All cases discussed provided increased information about the reactions if hormetic features were included. In only the shigatoxin case was there clear irrefutable evidence that beneficial hormetic properties exist and must be considered; however, the one-in-six advantage is too great to ignore the potential benefits of hormesis. We recommend such hormetic properties be considered together with conventional dose responses to improve estimates of chemical risk.

Invited response to definition of hormesis (EJ Calabrese and LA Baldwin).

Calabrese and Baldwin have proposed the Theory of Hormesis to explain a variety of disparate data. We evaluated the explanation using examples of pulmonary injury, radiation injury to white blood cells and selenium as an essential element, reducer of carcinogenesis and a potential toxicant. Calabrese and Baldwin have fulfilled many of the criteria allowing generalizability of their theory. They have gathered data extensively. These data were logically consistent with their experiences. They needed to examine critically the theory and any theories competing with it. At this point, each theory must be proved, disproved or its limitations clearly stated. It is in this phase that most work is still being accomplished. This examination is important because it provides referents for vigorous outside criticism, the final phase. Calabrese and Baldwin are to be complimented on seeking outside comment. Considerable refinement of the theory has taken place with time.

Digital papillomatosis in a confined Beagle.

Papillomavirus-induced papillomas were diagnosed on multiple digits of all 4 feet of a young Beagle. No other cutaneous or oral involvement was identified. Papillomavirus antigen was confirmed by immunoperoxidase localization within keratinocyte nuclei. In addition to the typical basophilic intranuclear inclusions associated with papillomavirus infections, keratinocytes within the papillomas contained large, eosinophilic cytoplasmic inclusions that previously have been described in a Boxer with cutaneous lesions associated with a papillomavirus infection. The papillomas in this Beagle regressed completely within 2 months of the initial diagnosis.

Plasmid and chromosomal basis of tolerance to cadmium and resistance to antibiotics in normal bovine duodenal bacterial flora.

Cadmium (Cd) tolerance and antibiotic resistance was studied in duodenal flora of 20 normal bovine samples. Twelve bacterial isolates (5 Staphylococcus spp, 4 Enterococcus faecalis, 2 Bacillus spp, and a Pseudomonas sp) were grown in Luria broth containing 0.05 to 0.8 mM of cadmium chloride (CdCl). All isolates displayed multiple antibiotic resistance, with 2 Enterococcus strains and Pseudomonas pickettii demonstrating resistance to 12/17 antibiotics tested. With the exception of Staphylococcus sp, all contained plasmid DNA. Curing to remove plasmid DNA determined if Cd tolerance and/or antibiotic resistance was plasmid or chromosomally mediated. None of the bacteria became sensitive to CdCl after curing, suggesting that tolerance was not plasmid-mediated. Six bacteria became sensitive to antibiotics after curing indicating that antibiotic2 resistance was plasmid mediated. Two of these bacteria became sensitive to multiple antibiotics; a Staphylococcus sp became sensitive to ampicillin, ceftiofur and cephalothin, and a Enterococcus strain became sensitive to neomycin, oxacillin, and tiamulin. All of the isolates were probed for the presence of known Cd-resistance genes (cadA, cadC, and cadD). DNA-DNA hybridization revealed cadA- and cadC-related sequences in chromosomal DNA of a Staphylococcus sp, an Enterococcus strain, and in plasmid DNA of another Staphylococcus sp. No cadD-related sequences were detected in any of the 12 isolates even under reduced stringency of hybridization.

Cholinesterase activity:muscarinic receptor ratios in canine and feline brains.

In response to findings that brain cholinesterase (ChE): muscarinic cholinergic receptor density (mChR) ratio is highly conserved between bird species (I), this study investigated the conservation of brain ChE:mChR between 2 mammalian species. Whole brains of 7 normal greyhounds, 14 normal non-greyhound dogs, and 8 normal cats, were assayed for ChE, mChR and protein. The same assays were made on cerebrum, cerebellum and brainstem from the greyhounds and 6 of the non-greyhound dogs. The Ellman assay was used to measure serum ChE activity, mChR were labelled with tritiated quinuclidinyl benzilate, and protein was measured by Lowry assay. Brain ChE:mChR was not highly conserved between the species. There was a statistically significant difference in brain mChR between greyhounds and non-greyhounds but this did not translate to a statistically significant difference in mean ChE:mChR. Measurement of ChE:mChR is unlikely to be useful in endangered carnivores for which normal ChE levels are unknown, because it cannot be assumed that endangered species would have the same ChE:mChR as their domestic relatives.

Pulmonary diseases caused by airborne contaminants in swine confinement buildings.

Exposure to toxic gases and particles or dusts while working or living in confinement animal systems pose a pulmonary health hazard. The severity of lung impairment from exposure to such environment is investigated using intratracheal instillation, intratracheal nebulization, and inhalation procedures. Ability to deliver particles with intratracheal instillation that are evenly distributed throughout the lung depends on the material used for injection. Pulmonary histopathology reflects anatomic changes following inhalation or instillation of chemicals or particles. Endobronchial saline washings of bronchioles and alveoli allow measurement of markers of pulmonary inflammation such as total nucleated cell (leukocyte) counts and those of macrophages, neutrophils and lymphocytes; TNF-alpha, and collagen concentration are used to further evaluate pulmonary response to endotoxin or dust exposure. Alveolar epithelial cells have an important role in clearing pulmonary fluid and maintaining the structure of lung tissue. After repeated exposure, damage to epithelial cells may result in their death, causing edema and collagen deposition that may lead to fibrosis.

Are 2,3-dimercapto-1-propanesulfonic acid or prussian blue beneficial in acute thallotoxicosis in rats?

Unithiol (2,3-dimercapto-I-propanesulfonic acid, DMPS) and prussian blue (potassium ferric hexacyanoferrate (II), PB), given alone or in combination, were evaluated as antidotes to treat acute thallotoxicosis in male Sprauge-Dawley rats. Animals were poisoned with 20 mg thallium (TI)/ kg bw PO on day 0 using thallous sulfate. On day 1 (24 h later), treatments began and were continued through day 4 as follows: 50 mg PB/kg bw PO, 2/ d; 5 mg DMPS/kg bw IP, 6/d (day 1), 4/d (day 2), 2/d (days 3-4); or the combination. Animals were sacrificed 24 h after the last treatment (day 5), and TI concentrations in kidney, liver, heart, brain, whole blood and feces determined by electrothermal atomic absorption spectroscopy. The relative accumulation of TI was kidney>>heart>liver approximately equal brain. PB limited incorporation of TI in all tissues. DMPS failed to significantly decrease TI in any organ, but significantly decreased TI in whole blood. PB+DMPS treatment significantly decreased the TI content in all organs, but not to a greater extent than PB alone. PB and PB+DMPS treatments significantly increased TI in feces, whereas DMPS alone produced little effect. This study confirms that PB is beneficial in the treatment of acute thallotoxicosis in rats. The failure of DMPS to significantly affect TI in target organs suggests it is not useful in treating TI poisoning.

Pseudomonas pickettii: a common soil and groundwater aerobic bacteria with pathogenic and biodegradation properties.

Pseudomonas pickettii is an aerobic, nonfermentative, Gram-negative rod-shaped, bacterium that has been isolated from soil, water, humans, and recently the bovine intestinal tract. It belongs to the rRNA group II of the genus Pseudomonas and has three biovars: Va-1, Va-2, and biovar 3/thomasii. P. pickettii can cause pneumonia, meningitis, endocarditis, and osteomyelitis in humans. It frequently is associated with nosocomial infections that often are linked to contaminated injectable solutions. P. pickettii exhibits remarkable ability to degrade a variety of toxic compounds such as chlorophenols, aromatic hydrocarbons, 2,4-dichlorophenoxyacetic acid, and pentacyclic triterpeniod compounds. The genes that encode for these properties are chromosome- and plasmid-associated. Strains of the organism also have demonstrated resistance to heavy metals, such as cadmium, copper, and zinc. This species can survive in a nutrient-poor environment and use a variety of toxic compounds as carbon and energy sources, making it an ideal candidate for study in the biodegradation of toxic compounds found in wastewater and soils.

Microbial resistance to metals in the environment.

Many microorganisms demonstrate resistance to metals in water, soil and industrial waste. Genes located on chromosomes, plasmids, or transposons encode specific resistance to a variety of metal ions. Some metals, such as cobalt, copper, nickel, serve as micronutrients and are used for redox processes, to stabilize molecules through electrostatic interactions, as components of various enzymes, and for regulation of osmotic pressure. Most metals are nonessential, have no nutrient value, and are potentially toxic to microorganisms. These toxic metals interact with essential cellular components through covalent and ionic bonding. At high levels, both essential and nonessential metals can damage cell membranes, alter enzyme specificity, disrupt cellular functions, and damage the structure of DNA. Microorganisms have adapted to the presence of both nutrient and nonessential metals by developing a variety of resistance mechanisms. Six metal resistance mechanisms exist: exclusion by permeability barrier, intra- and extra-cellular sequestration, active transport efflux pumps, enzymatic detoxification, and reduction in the sensitivity of cellular targets to metal ions. The understanding of how microorganisms resist metals can provide insight into strategies for their detoxification or removal from the environment.

An analysis of the chronic oral toxicity of polyether ionophore antibiotics in animals.

Feeding well-mixed ionophores to adapted cattle improves ruminal fermentation and growth rates. In nonruminants, growth is improved by reducing competing gastrointestinal microorganisms. Interactions of monensin with other drugs may be beneficial or toxic. Tiamulin and furazolidone potentiate monensin's negative effects. For example, monensin produces positive inotropy and cardiomyopathy dependent on calcium and extracellular sodium. Based on available toxicity data and derived no observable effect levels (NOEL) in the same species and across species, monensin was more toxic than salinomycin, lasalocid or narasin. Lasalocid was 5- to 10-fold less toxic to horses than is monensin. Based on available toxicity data and derived NOEL, lasalocid was less toxic than all ionophores except salinomycin. Very high levels of narasin caused death in sows, leg muscle weakness in turkeys, and cardiopulmonary clinical signs in 15% of the rabbits from Brazilian rabbit farms. Only salinomycin and lasalocid were less toxic than narasin. Salinomycin was the least toxic of all the ionophores. Maduramicin was the most toxic of all the ionophores. Nearly all maduramicin fed to poultry persists in litter (manure), making this poultry litter toxic if fed to cattle as a nitrogen source. While ionophore comparative toxicity was difficult to estimate, most cross-comparisons utilized NOEL within and across species. The relative toxicities of the ionophores from lowest to highest were salinomycin < lasalocid < or = narasin < or = monensin (but lasalocid < monensin) < maduramicin.

The presence of a muscarinic receptor on canine erythrocyte membranes.

Muscarinic receptors were present on erythrocyte ghosts of the domestic dog (Canis familiaris) at a concentration of 0.61 nmol/mg protein, and had a KD of 62.5 nmol. Properties including a mean nonspecific binding of 80%, the high risk that adherence of additional molecules of radioligand would occur, and the necessity for extensive dilution of erythrocyte ghosts to obtain a practical quantity of muscarinic receptors, lead us to conclude that the canine erythrocyte ghost is not an efficient or practical model to study muscarinic receptors and their interactions with cholinergic agonists or antagonists.

Deer velvet antler: some unanswered questions on toxicology.

Deer velvet antler is marketed as a remedy for a wide range of disorders. However, there is a lack of information in the scientific literature to support these claims, and there is also a lack of information on potential toxicity. Areas of potential concern include drug residues, possible deleterious androgenic effects on fetuses and neonates and allergic reactions.

Toxicosis in cattle from concurrent feeding of monensin and dried distiller's grains contaminated with macrolide antibiotics.

Consumption of monensin-containing feed contaminated with macrolide antibiotic residues resulted in the death of cattle from multiple feedlots in south-central Kansas. Cattle were fed milo dried distiller's grains (DDG) with solubles from a common source in conjunction with the ionophore antibiotic, monensin. Deaths occurred as early as 72-96 hours after feeding and were preceded by either no premonitory signs or 1 or more of the following: anorexia, depression, dyspnea, locomotor deficits, and recumbency. Significant gross lesions were pulmonary and mesenteric edema, hepatomegaly, and generalized myocardial and skeletal muscle pallor that was confirmed histologically as acute myodegeneration and necrosis. Other significant histologic lesions included centrolobular hepatocellular necrosis, congestion, and pulmonary interstitial and alveolar edema with fibrin exudation. Animals that survived beyond 6 weeks had poor weight gain and coalescing foci of myocardial fibrosis with residual myocardial degeneration. Analysis of trace mineral supplements for monensin were within the manufacturer's label range. The DDG samples from affected feedlots had 50-1,500 ppm of erythromycin, clarithromycin, and related macrolide antibiotic analogues, which originated in the alcohol residue. In a preliminary feeding trial, cattle fed this contaminated DDG in combination with monensin had clinical signs and died with gross and histologic findings comparable to those of the field cases. Even though rations supplemented with the contaminated DDG contained approved levels of monensin, the clinical and postmortem findings were consistent with those expected for monensin toxicosis. The presence of macrolide antibiotic residues in the contaminated feed appeared to affect the biotransformation of otherwise nontoxic levels of monensin, leading to clinical ionophore toxicosis.

Detection of metabolites of a veterinary counter-irritant in canine urine.

Routine paper chromatographic screening of the urine of racing greyhounds exposed to BIGELOIL, a veterinary counter-irritant, revealed metabolites suggestive of menthol, an ingredient of BIGELOIL. To determine whether BIGELOIL use caused these metabolites, 2 Dalmatian dogs were exposed to BIGELOIL. Thin-layer chromatographic screening of their urine confirmed that exposure to BIGELOIL by either dermal or oral routes causes the same metabolites as those observed in the racing greyhounds. Metabolites suggestive of thymol were also present in some samples. We conclude that, if metabolites suggestive of menthol are detected in urine of animal athletes, further analysis for the other performance-affecting ingredients of BIGELOIL should be undertaken.

A safety study of thallium-containing ceramic superconductor material in rats.

Thallium is a highly toxic cumulative poison in humans and animals. The use of the metal as a component in ceramic superconductor material (CSM) raised concern about the health risk of CSM to children accidentally swallowing some of the CSM or to occupationally-exposed workers in the electronics industry. This study examined the biological availability of CSM by quantifying the thallium content in organs, blood and fecal matter of Sprague-Dawley rats after a single acute oral exposure to CSM and compares these values to similar thallium measurements from identical exposure to thallium sulfate. The CSM-exposed group had significantly less thallium than the thallium sulfate-exposed group in all tissues/fluids analyzed. This suggested that CSM poses a lower health risk to exposed persons than thallium sulfate.

Stability of water nitrate levels during prolonged boiling.

The stability of nitrate in boiling water was examined. No changes in nitrate concentrations occurred when 100 and 500 ppm potassium nitrate solutions were boiled for up to 24 h.