Methylated arsenicals: the implications of metabolism and carcinogenicity studies in rodents to human risk assessment

Monomethylarsonic acid (MMA(V)) and dimethylarsinic acid (DMA(V)) are active ingredients in pesticidal products used mainly for weed control. MMA(V) and DMA(V) are also metabolites of inorganic arsenic, formed intracellularly, primarily in liver cells in a metabolic process of repeated reductions and oxidative methylations. Inorganic arsenic is a known human carcinogen, inducing tumors of the skin, urinary bladder, and lung. However, a good animal model has not yet been found. Although the metabolic process of inorganic arsenic appears to enhance the excretion of arsenic from the body, it also involves formation of methylated compounds of trivalent arsenic as intermediates. Trivalent arsenicals (whether inorganic or organic) are highly reactive compounds that can cause cytotoxicity and indirect genotoxicity in vitro. DMA(V) was found to be a bladder carcinogen only in rats and only when administered in the diet or drinking water at high doses. It was negative in a two-year bioassay in mice. MMA(V) was negative in 2-year bioassays in rats and mice. The mode of action for DMA(V)-induced bladder cancer in rats appears to not involve DNA reactivity, but rather involves cytotoxicity with consequent regenerative proliferation, ultimately leading to the formation of carcinoma. This critical review responds to the question of whether DMA(V)-induced bladder cancer in rats can be extrapolated to humans, based on detailed comparisons between inorganic and organic arsenicals, including their metabolism and disposition in various animal species. The further metabolism and disposition of MMA(V) and DMA(V) formed endogenously during the metabolism of inorganic arsenic is different from the metabolism and disposition of MMA(V) and DMA(V) from exogenous exposure. The trivalent arsenicals that are cytotoxic and indirectly genotoxic in vitro are hardly formed in an organism exposed to MMA(V) or DMA(V) because of poor cellular uptake and limited metabolism of the ingested compounds. Furthermore, the evidence strongly supports a nonlinear dose-response relationship for the biologic processes involved in the carcinogenicity of arsenicals. Based on an overall review of the evidence, using a margin-of-exposure approach for MMA(V) and DMA(V) risk assessment is appropriate. At anticipated environmental exposures to MMA(V) and DMA(V), there is not likely to be a carcinogenic risk to humans.     

Comparative acute toxicity of potassium permanganate to nontarget aquatic organisms

Potassium permanganate (KMnO4) is used worldwide in freshwater pond aquaculture for treatment and prevention of waterborne external parasitic, bacterial, and fungal diseases. Nevertheless, KMnO4 has not been approved by the U.S. Food and Drug Administration, and insufficient information exists to allow evaluation of the environmental risk of KMnO4 exposures. Limited data exist concerning KMnO4 toxicity to nontarget species in systems receiving aquaculture effluent from treated ponds. The goal of this research is to generate effects data for use in developing an ecological risk assessment of KMnO4. Toxicity tests were used to compare the relative sensitivities of five standard aquatic test species to KMnO4. Acute toxicity test results using synthetic moderately hard water show static 96-h mean median lethal concentration (LC50) values +/- standard deviation (SD) of 0.058 +/- 0.006 mg/L for Ceriodaphnia dubia, 0.053 +/- 0.009 mg/L for Daphnia magna, 2.13 +/- 0.07 mg/L for Pimephales promelas, 4.74 +/- 1.05 mg/L for Hyalella azteca, and 4.43 +/- 0.79 mg/L for Chironomus tentans. Most of these values are below the recommended KMnO4 treatment rate of at least 2.0 mg/L or 2.5 times the water's potassium permanganate demand (PPD; an estimation of the available reducing agents in the exposure water), suggesting significant environmental risk. However, repeating these laboratory tests using pond water resulted in significantly reduced toxicity, with static 96-h mean LC50 values (+/-SD) of 2.39 +/- 0.36 mg/L for C. dubia, 1.98 +/- 0.12 mg/L for D. magna, 11.22 +/- 1.07 mg/L for P. promelas, 13.55 +/- 2.24 mg/L for H. azteca, and 12.30 +/- 2.83 mg/L for C. tentans. The PPD of synthetic moderately hard water was 0.329 +/- 0.114 mg/L; however, pond water PPD was 5.357 +/- 0.967 mg/L. The effective disease-treating dose based on 2.5 times the PPD would thus be 0.823 and 13.392 mg KMnO4/L, respectively, exceeding the LC50 for most of these nontarget organisms, even in pond water, immediately after treatment.     

Nonsupplemented children of Latino immigrants have low vitamin E intakes and plasma concentrations and normal vitamin C, selenium, and carotenoid intakes and plasma concentrations

OBJECTIVE: This study sought to determine and evaluate the intakes and plasma concentrations of vitamin E (alpha-tocopherol), gamma-tocopherol, vitamin C, selenium, and carotenoids (alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein/zeaxanthin, and lycopene) of nonsupplemented boys and girls, 4 to 8 years old, of Latino immigrants living in rural Nebraska. DESIGN: Dietary intakes of the Latino children were estimated. Their plasma samples (fasting) were analyzed for vitamin E, vitamin C, selenium, and carotenoid concentrations. Data were evaluated by sex. SUBJECTS: The subjects were a convenience sample of 4- to 8-year-old (n=29), apparently healthy, nonsupplemented children of Latino immigrants living in rural Nebraska. STATISTICAL ANALYSIS: Sex differences in parameter values were determined using general linear models; Pearson r was used for determining correlations. RESULTS: No significant differences in parameter values were observed by sex, with the exception of plasma lutein/zeaxanthin concentration. The majority (69%) had plasma vitamin E (alpha-tocopherol) concentrations<0.516 mg/dL (12 micromol/L), which is indicative of vitamin E inadequacy, and over half (59%) reported consuming less than the Estimated Average Requirement for vitamin E. All subjects had plasma vitamin C and selenium concentrations indicative of adequacy (>0.41 mg/dL or >23 micromol/L, and >6.32 microg/dL or >0.8 micromol/L, respectively), and consumed at least the Recommended Dietary Allowances for these nutrients. The plasma carotenoid concentrations of the children may be useful as norms. CONCLUSIONS: These children of Latino immigrants who did not take supplements had low plasma vitamin E (alpha-tocopherol) concentrations but normal plasma vitamin C and selenium concentrations. IMPLICATIONS: Dietetics professionals and others involved in health care need to work with Latino immigrant parents so that their children consume adequate amounts of vitamin E.     

Outbreak bias in illness reporting and case confirmation in ciguatera fish poisoning surveillance in south Florida

OBJECTIVE: Ciguatera fish poisoning is a potentially life-threatening disease caused by eating coral reef fish contaminated with ciguatoxins and is the most common marine poisoning. However, existing surveillance systems capture few cases. To improve regional ciguatera surveillance in South Florida, this study compared ciguatera illnesses in the Florida Poison Information Center-Miami (FPICM) call database to ciguatera cases in the Florida Department of Health (FDOH) disease surveillance systems. METHODS: Univariate and multivariate logistic regression were used to identify predictors of when FPICM reported ciguatera illnesses to FDOH and whether FDOH confirmed reported ciguatera cases. RESULTS: FPICM staff preferentially reported ciguatera illnesses that were of shorter duration (adjusted odds ratio [AOR] = 0.84 per additional illness day; 95% confidence interval [CI] 0.74, 0.97); outbreak-associated (AOR = 7.0; 95% CI 2.5, 19.5); and clinically more severe (AOR = 21.6; 95% CI 2.3, 198.5). Among ciguatera illnesses reported to FDOH, outbreak-associated illnesses were more likely than single, sporadic illnesses to become confirmed surveillance cases (crude OR = 11.1; 95% CI 2.0, 62.5). CONCLUSIONS: The over-representation of outbreak-associated ciguatera cases underestimates the true contribution of sporadic illnesses to ciguatera disease burden. This bias should be considered when evaluating surveillance systems that include both outbreak-associated and sporadic illness reports.     

Bone loss and muscle atrophy in spinal cord injury: epidemiology, fracture prediction, and rehabilitation strategies

Individuals with spinal cord injury (SCI) often experience bone loss and muscle atrophy. Muscle atrophy can result in reduced metabolic rate and increase the risk of metabolic disorders. Sublesional osteoporosis predisposes individuals with SCI to an increased risk of low-trauma fracture. Fractures in people with SCI have been reported during transfers from bed to chair, and while being turned in bed. The bone loss and muscle atrophy that occur after SCI are substantial and may be influenced by factors such as completeness of injury or time postinjury. A number of interventions, including standing, electrically stimulated cycling or resistance training, and walking exercises have been explored with the aim of reducing bone loss and/or increasing bone mass and muscle mass in individuals with SCI. Exercise with electrical stimulation appears to increase muscle mass and/or prevent atrophy, but studies investigating its effect on bone are conflicting. Several methodological limitations in exercise studies with individuals with SCI to date limit our ability to confirm the utility of exercise for improving skeletal status. The impact of standing or walking exercises on muscle and bone has not been well established. Future research should carefully consider the study design, skeletal measurement sites, and the measurement techniques used in order to facilitate sound conclusions.     

Phylogenetic analysis of classical swine fever virus (CSFV) field isolates from outbreaks in South and Central America

To date, there is little information concerning the epidemiological situation of classical swine fever (CSF) in the Americas. Besides summarizing the available data, genotyping of isolates from outbreaks in domestic pigs in several countries of South and Central America was performed. For this, a 190 base fragment of the E2 envelope glycoprotein gene was used. European strains and isolates, and historical isolates from the United States (US) were included for comparison. In contrast to the situation in most parts of Europe, where group 2 isolates predominate, it was found that all the isolates from the American continent analyzed belonged to group 1 and were further resolved into three subgroups. The Cuban isolates clustered in subgroup 1.2, whereas the isolates from Honduras and Guatemala clustered in subgroup 1.3. The remaining isolates from Argentina, Brazil, Colombia and Mexico generated four poorly resolved clusters in subgroup 1.1, together with the vaccine strains, with historical European and US isolates, and with a recent Russian isolate. While the vaccine strains and the historical European isolates formed a relatively distinct cluster, one of the US isolates clustered together with the Mexican, and another one with Colombian isolates. Historically, CSF (hog cholera) was observed almost simultaneously in the US and in Europe in the first half of the 19th century, and its origin remains a matter of discussion. Our results showed that the US isolates are closely related to isolates from South America, while appearance of isolates in Cuba on one hand and in Honduras and Guatemala on the other hand, seems to have been due to unrelated events. This allows to speculate that at least in the American continent, CSF virus may have appeared independently in several regions, and spreading may have been a secondary effect.     

Gender-dependent effects of fluoxetine on selected biochemical parameters in guinea pigs

Gender-related changes in plasma chemistry values were examined in guinea pigs after taking oral fluoxetine hydrochloride (HCl) as a widely prescribed drug for weight reduction and treatment of depressive disorders. Twenty guinea pigs of both sexes were divided into four groups of five animals. For both of the sexes, one group was treated with oral fluoxetine HCl (20?mg/kg/day) and another was used as a control which administered with distilled water. On the last day of the experiment (35th day), blood samples were collected for determining selected plasma biochemical parameters. For lipid profile, increases in high-density lipoprotein cholesterol, very low-density lipoprotein-cholesterol, and triglycerides were seen in both sexes, along with increases in total cholesterol and low-density lipoprotein cholesterol (LDL-C) in males and decreases of LDL-C in females and atherogenic index in both sexes. The levels of total protein, globulins, urea, and creatinine were increased only in the male guinea pigs that received fluoxetine. Although, the levels of creatine phosphokinase and alanine transaminase decreased in the fluoxetine-treated female guinea pigs compared to control. Other parameters like lactate dehydrogenase, alkaline phosphatase, aspartate transaminase, albumin, total bilirubin, (in)direct bilirubin, fasting blood sugar, calcium, and phosphorus did not alter following intake of fluoxetine in both sexes. For hormonal profile, testosterone and tetraiodothyronine (T4) in males and T3 and thyroid-stimulating hormone in both sexes did not change in fluoxetine-treated guinea pigs. However, the level of T4 decreased in fluoxetine-treated female group compared with the control group. Fluoxetine treatment resulted in gender-dependent effects. The decrease of T4 in female guinea pigs that received fluoxetine supports that this drug would be a possible endocrine disruptor.