Asheesh K. Tiwary

Comparative Toxicosis of Sodium Selenite and Selenomethionine in Lambs

Excess consumption of selenium (Se) accumulator plants can result in selenium intoxication. The objective of the study reported here was to compare the acute toxicosis caused by organic selenium (selenomethionine) found in plants with that caused by the supplemental, inorganic form of selenium (sodium selenite). Lambs were orally administered a single dose of selenium as either sodium selenite or selenomethionine and were monitored for 7 days, after which they were euthanized and necropsied. Twelve randomly assigned treatment groups consisted of animals given 0, 1, 2, 3, or 4 mg of Se/kg of body weight as sodium selenite, or 0, 1, 2, 3, 4, 6, or 8 mg of Se/kg as selenomethionine. Sodium selenite at dosages of 2, 3, and 4 mg/kg, as well as selenomethionine at dosages of 4, 6, and 8 mg/kg resulted in tachypnea and/or respiratory distress following minimal exercise. Severity and time to recovery varied, and were dose dependent. Major histopathologic findings in animals of the high-dose groups included multifocal myocardial necrosis and pulmonary alveolar vasculitis with pulmonary edema and hemorrhage. Analysis of liver, kidney cortex, heart, blood, and serum revealed linear, dose-dependent increases in selenium concentration. However, tissue selenium concentration in selenomethionine-treated lambs were significantly greater than that in lambs treated with equivalent doses of sodium selenite. To estimate the oxidative effects of these selenium compounds in vivo, liver vitamin E concentration also was measured. Sodium selenite, but not selenomethionine administration resulted in decreased liver vitamin E concentration. Results of this study indicate that the chemical form of the ingested Se must be known to adequately interpret tissue, blood, and serum Se concentrations.

Case report : Potential arsenic toxicosis secondary to herbal kelp supplement

Context Medicinal use of dietary herbal supplements can cause inadvertent arsenic toxicosis. Case Presentation A 54-year-old woman was referred to the University of California, Davis, Occupational Medicine Clinic with a 2-year history of worsening alopecia and memory loss. She also reported having a rash, increasing fatigue, nausea, and vomiting, disabling her to the point where she could no longer work full-time. A thorough exposure history revealed that she took daily kelp supplements. A urine sample showed an arsenic level of 83.6 μg/g creatinine (normal < 50 μg/g creatinine). A sample from her kelp supplements contained 8.5 mg/kg (ppm) arsenic. Within weeks of discontinuing the supplements, her symptoms resolved and arsenic blood and urine levels were undetectable. Discussion To evaluate the extent of arsenic contamination in commercially available kelp, we analyzed nine samples randomly obtained from local health food stores. Eight of the nine samples showed detectable levels of arsenic higher than the Food and Drug Administration tolerance level of 0.5 to 2 ppm for certain food products. None of the supplements contained information regarding the possibility of contamination with arsenic or other heavy metals. The 1994 Dietary Supplement Health and Education Act (DSHEA) has changed the way dietary herbal therapies are marketed and regulated in the United States. Less regulation of dietary herbal therapies will make inadvertent toxicities a more frequent occurrence. Relevance to Clinical Practice Clinicians should be aware of the potential for heavy metal toxicity due to chronic use of dietary herbal supplements. Inquiring about use of dietary supplements is an important element of the medical history.

Diagnosis of Taxus (Yew) Poisoning in a Horse

A 2-year-old bay Thoroughbred colt was found dead overnight in its stall without a known history of any illness, existing disease, or toxicant exposure. No information on the clinical signs before this animals death was reported. A full necropsy was performed the next morning and revealed a mild to moderate degree of endocardial hemorrhages in both ventricles. Microscopic examination of the heart showed an acute mild mutifocal necrosis of papillary muscles and ventricles. The stomach content contained approximately 2% Taxus alkaloids as determined by gas chromatography/mass spectrometry. In the past, diagnosis of Taxus poisoning has been mainly based on history of exposure and the presence of plant parts in the gastrointestinal tract. Pathological lesions associated with Taxus poisoning have not been published for horses. Therefore, this is the first report of cardiac lesions in a horse after lethal exposure to Taxus. On the basis of these findings, it is suggested that Taxus exposure needs to be considered in the differential diagnosis of horses that die suddenly or have cardiac lesions suggestive of Taxus exposure, even if intact plant parts are not identified in the stomach by the naked eye.

Coordinated regulation of murine cardiomyocyte contractility by nanomolar (-)-epigallocatechin-3-gallate, the major green tea catechin.

Green tea polyphenolic catechins exhibit biological activity in a wide variety of cell types. Although reports in the lay and scientific literature suggest therapeutic potential for improving cardiovascular health, the underlying molecular mechanisms of action remain unclear. Previous studies have implicated a wide range of molecular targets in cardiac muscle for the major green tea catechin, (−)-epigallocatechin-3-gallate (EGCG), but effects were observed only at micromolar concentrations of unclear clinical relevance. Here, we report that nanomolar concentrations of EGCG significantly enhance contractility of intact murine myocytes by increasing electrically evoked Ca2+ transients, sarcoplasmic reticulum (SR) Ca2+ content, and ryanodine receptor type 2 (RyR2) channel open probability. Voltage-clamp experiments demonstrate that 10 nM EGCG significantly inhibits the Na+-Ca2+ exchanger. Of importance, other Na+ and Ca2+ handling proteins such as Ca2+-ATPase, Na+-H+ exchanger, and Na+-K+-ATPase were not affected by EGCG ≤1 μM. Thus, nanomolar EGCG increases contractility in intact myocytes by coordinately modulating SR Ca2+ loading, RyR2-mediated Ca2+ release, and Na+-Ca2+ exchange. Inhibition of Na+-K+-ATPase activity probably contributes to the positive inotropic effects observed at EGCG concentrations >1 μM. These newly recognized actions of nanomolar and micromolar EGCG should be considered when the therapeutic and toxicological potential of green tea supplementation is evaluated and may provide a novel therapeutic strategy for improving contractile function in heart failure.

Using Roquefortine C as a Biomarker for Penitrem A Intoxication

Penitrem A is a well-recognized tremorgenic mycotoxin produced by several Penicillium spp. However, most natural cases of penitrem A intoxication have been associated with Penicillium crustosum. Another Penicillium sp., Penicillium roqueforti, is used for the production of blue cheese and is found in silage and feeds. Penicillium roqueforti produces a mycotoxin, roquefortine C, which is also produced by P. crustosum. In contrast to a tremorgenic syndrome produced by penitrem A, roquefortine C toxicosis is characterized by a paralytic syndrome. Two cases of penitrem A intoxication in dogs are presented to investigate the use of roquefortine C as a biomarker for penitrem A exposure. The vomitus, serum, and urine were analyzed for roquefortine C and penitrem A. Results suggest that roquefortine C can be a sensitive biomarker for penitrem A intoxication. However, the detection of roquefortine C in the absence of penitrem A could merely suggest ingestion of blue cheese or spoilt silage or feed. A review of the literature did not identify any case positive for penitrem A but negative for roquefortine C. In cases in which both mycotoxins were detected, roquefortine C concentration was always higher than penitrem A concentration. In contrast, several cases have been described where the clinical history suggested penitrem A intoxication, but only roquefortine C was detected. In conclusion, roquefortine C can serve as a sensitive biomarker for penitrem A intoxication, but the clinical presentation needs to be considered for proper interpretation of its detection in the absence of penitrem A.

In vitro study of the effectiveness of three commercial adsorbents for binding oleander toxins

Introduction: Oleander (Nerium oleander) poisoning is a common problem found in many parts of the world. The oleander toxicity is due to oleandrin and its aglycone metabolite oleandrigenin. Activated charcoal is a useful gastrointestinal decontamination agent that limits the absorption of ingested toxins. A relatively new clay product, Bio-SpongeTM, containing di-tri-octahedral smectite as the active ingredient, is also recommended for adsorbing bacterial toxins in the gastrointestinal tract. Bio-SpongeTM has been used to prevent gastrointestinal absorption of oleander toxins in livestock but the efficacy of activated charcoal and Bio-SpongeTM for adsorbing oleandrin and oleandrigenin has not yet been studied. Methods: An in vitro experiment to compare the efficacy of three commercially available adsorbents was performed. The adsorbents include Bio-SpongeTM, ToxiBanTM granules, and a generic grade activated charcoal. Results: ToxiBanTM granules have the highest adsorptive capacity, followed by the generic grade activated charcoal, and finally, Bio-SpongeTM. Discussion: Bio-SpongeTM did not adsorb oleandrin and oleandrigenin at concentrations that are expected to be present in the gastrointestinal tract of poisoned animals. Conclusions: On the basis of this in vitro study, products containing activated charcoal are more effective for binding oleander toxins and providing gastrointestinal decontamination than products containing di-tri-octahedral smectite. However, the ability of these adsorbents to alter the clinical outcome in oleander-poisoned animals or humans is yet to be evaluated.

Comparative oral dose toxicokinetics of sodium selenite and selenomethionine

Selenium (Se) poisoning by different forms of Se occurs in the United States. However, the toxicokinetics of different selenocompounds after oral ingestion is not well documented. In this study the toxicokinetics of Se absorption, distribution and elimination were determined in serum and whole blood of lambs that were orally dosed with increasing doses of Se as sodium selenite (inorganic Se) or selenomethionine (SeMet, organic Se). Thirty‐two lambs were randomly assigned to eight treatment groups, with four animals per group. Se was administered at 1, 2 or 3 mg kg−1 body weight, as either sodium selenite or SeMet with proper control groups. Blood and serum were collected at predetermined time points for 7 days post‐dosing. Resulting Se concentrations in both serum and whole blood from SeMet treatment groups were significantly greater than those given equimolar doses of Se as sodium selenite. Se concentrations in serum and whole blood of lambs dosed with SeMet peaked at significantly greater concentrations when compared with lambs dosed with equimolar doses of sodium selenite. Based on the serum and whole blood kinetics, the rate of Se absorption was greater for SeMet than for sodium selenite although rates of absorption for both Se forms decreased with increasing dose. The rates of Se elimination increased with dose. These results demonstrate that SeMet has a greater absorption rate and a similar retention time resulting in a greater area under the curve and thus bioavailability than sodium selenite, which must be considered in both overdose and nutritional exposures. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Arsenic in Herbal Kelp Supplements: Schenker et al. Respond

We are heartened by the feedback we have received from concerned patients, health-care professionals, herbal supplement retailers, and government health officials regarding our recent case study (Amster et al. 2007), but we certainly understand the concern from the representatives of the herbal trade industry. We would like to take this opportunity to respond to some of their comments. In their letter, McGuffin and Dentali suggest that iodine was the cause of our patient’s symptoms, a conclusion with which we disagree. Daily intake of up to 500 μg iodine does not clinically affect the thyroid. Although it has been suggested that 1–2 mg/day is safe, there is also evidence that much higher intakes are tolerated without problems. In their comprehensive review of this subject, Backer and Hollowell (2000) concluded that “the strongest data suggest that low levels of iodine (1–5 mg/day) are safe for most people for years.” The 10th edition of the Recommended Dietary Allowances (National Research Council 1989) suggested a maximum allowable dietary intake of iodine of 2 mg/day for adults, and Breecher and Dworken (1986) noted that chronic toxicity develops only when intake is > 2 mg/day. Increased iodine intake (≤ 10 mg/day) may cause hypothyroidism or hyperthyroidism, but this condition is quite rare and is usually associated with underlying risk factors such as thyroiditis, subacute thyroiditis, or previously treated Graves disease. Intake of very high concentrations (18 mg to > 1 g/day) has been associated with iodine goiter (Wolff 1969). Although we wonder how many cases of hypothyroidism are caused by irresponsible supplement use, in our case iodine toxicity is not the most likely etiology. Our patient (Amster et al. 2007) had normal thyroid function tests on two different occasions when hypothyroidism was being considered. Furthermore, she fully recovered (especially memory loss and fatigue) within 3 weeks after discontinuation of the kelp supplement. This short span of time for recovery would most likely not occur if she had iodine-induced hypothyroidism. In summary, the clinical presentation of this case was not consistent with iodine toxicity, particularly at the dose ingested. It is our clinical opinion, given the supporting clinical history and laboratory evidence, that her symptoms were more likely from the arsenic found in her kelp supplement and not from iodine. We believe this case raises legitimate concerns about arsenic toxicosis from commercially available kelp supplements and that further testing is indicated. McGuffin and Dentali suggest that the patient is to blame for taking more than the recommended dose. We agree that the patient has ultimate responsibility to stay within the manufacturer’s guidelines, but we wonder if our patient may have been more careful in her self-prescribing if the presence of potentially toxic levels of heavy metals were included in the product labeling. This does, however, highlight a general concern of herbal medications as they are currently marketed and used: There is little oversight from prescribing health practitioners, and self-dosing commonly leads to overdosing and possible adverse herb–drug interactions (Bush et al. 2007). McGuffin and Dentali are correct that our reporting of the dietary supplement market share was indeed misstated. We reported

Diagnosis of Zinc Phosphide Poisoning in Chickens Using a New Analytical Approach

178 billion from the Nutrition Business Journal (Anonymous 2002), but

Evaluation of the respiratory elimination kinetics of selenium after oral administration in sheep.

17.8 billion is the correct figure. Our study (Amster et al. 2007) was not intended to be a comprehensive survey of arsenic content in commercial kelp supplements, but rather to call attention to the large variability of arsenic concentrations. In his letter, Lewis suggests, without documentation, that “the arsenic most commonly found in seaweed and seafood products is relatively nontoxic,” that is, organic arsenic. In a recent study on arsenic content in ethanolic kelp and bladderwrack extracts, Krishna et al. (Krishna MVB, Brewer TM, Marcus RK, unpublished data) found that the majority (90–95%) of the arsenic present was inorganic arsenic, and only minor amounts of arsenic (5–10% of the total arsenic) were dimethyl arsenic acid. This finding suggests that the majority of arsenic in kelp supplements is the more toxic inorganic arsenic. McGuffin and Dentali, representatives from the American Herbal Products Association, point out the difference between homeopathic and herbal therapies. We agree that there are differences, but for the purpose of our study there are obvious similarities: Both are used for medicinal purposes on a nonprescription basis and have been found to have toxic levels of heavy metals. McGuffin and Dentali are correct to point out that homeopathic medicines are regulated in a similar fashion to allopathic medicinals, as opposed to dietary supplements, which under the Dietary Supplement Health and Education Act of 1994 (DSHEA 1994) lack regulatory standards for premarket approval, good manufacturing standards, and labeling of indication (Borneman and Field 2006). In conclusion, it was in no way our intention to attack the complementary alternative medicine community. Fortunately we all agree that the supplement industry has a responsibility to control the level of potentially harmful contaminants in their products. However, if the majority of certain herbal supplements have detectable levels of toxic metals—as is the case in our and other studies on kelp—then perhaps we should not leave the responsibility to the industry itself, but instead encourage our government to regulate these medicinals the same as all other medications, and not as dietary supplements.