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Esophageal squamous cell carcinoma (ESCC) is an environment-relevant malignancy with a high mortality. Nitrosamines, a class of nitrogen-containing environmental carcinogens, are widely suggested as a risk factor for ESCC. However, how nitrosamines affect metabolic regulation to promote ESCC tumorigenesis is largely unknown. In this study, the transition trajectory of serum metabolism in the course of ESCC induced by N-nitrosomethylbenzylamine (NMBA) in rats was depicted by an untargeted metabolomic analysis, and the potential molecular mechanisms were revealed. The results showed that the metabolic alteration in rats was slight at the basal cell hyperplasia (BCH) stage, while it became apparent when the esophageal lesion developed into dysplasia (DYS) or more serious conditions. Moreover, serum metabolism of severe dysplasia (S-DYS) showed more similar characteristics to that of carcinoma in situ (CIS) and invasive cancer (IC). Aberrant nicotinate (NA) and nicotinamide (NAM) metabolism, tryptophan (TRP) metabolism, and sphingolipid metabolism could be the key players favoring the malignant transformation of esophageal epithelium induced by NMBA. More particularly, NA and NAM metabolism in the precancerous stages and TRP metabolism in the cancerous stages were demonstrated to replenish NAD + in different patterns. Furthermore, both the IDO1-KYN-AHR axis mediated by TRP metabolism and the SPHK1-S1P-S1PR1 axis by sphingolipid metabolism provided an impetus to create the pro-inflammatory yet immune-suppressive microenvironment to facilitate the esophageal tumorigenesis and progression. Together, these suggested that NMBA exerted its carcinogenicity via more than one pathway, which may act together to produce combination effects. Targeting these pathways may open up the possibility to attenuate NMBA-induced esophageal carcinogenesis. However, the interconnection between different metabolic pathways needs to be specified further. And the integrative and multi-level systematic research will be conducive to fully understanding the mechanisms of NMBA-induced ESCC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

1,4-Dihydropyridines (1,4-DHP) possess important biochemical and pharmacological properties, including antioxidant and antimutagenic activities. AV-153-Na, an antimutagenic and DNA-repair enhancing compound was shown to interact with DNA by intercalation. Here we studied DNA binding of several AV-153 salts to evaluate the impact of AV-153 modifications on its DNA binding capacity, the ability to scavenge the peroxynitrite, to protect HeLa and B-cells cells against DNA damage. Affinity of the AV-153 salts to DNA measured by a fluorescence assay was dependent on the metal ion forming a salt in position 4 of the 1,4-DHP, and it decreased as follows: Mg > Na > Ca > Li > Rb > K. AV-153-K and AV-153-Rb could not react chemically with peroxynitrite as opposed to AV-153-Mg and AV-153-Ca, the latter increased the decomposition rate of peroxynitrite. AV-153-Na and AV-153-Ca effectively reduced DNA damage induced by peroxynitrite in HeLa cells, while AV-153-K and AV-153-Rb were less effective, AV-153-Li did not protect the DNA, and AV-153-Mg even caused DNA damage itself. The Na, K, Ca and Mg AV-153 salts were also shown to reduce the level of DNA damage in human B-cells from healthy donors. Thus, metal ions modify both DNA-binding and DNA-protecting effects of the AV-153 salts., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The rise in pesticides application has increased the need for better understanding of their ecological impacts. The global amphibian declines, for example, have been positively correlated with pesticides use. The differential susceptibility in the developmental stages of amphibians to chemical substances are still largely unknown. We examined the 96-h differential toxicity responses of embryos, premetamorphic and transitional larval stage of Xenopus laevis, to six formulated aquatic herbicide products containing the active ingredients of diquat dibromide (Midstream), glufosinate ammonium (Basta), imazapyr (Arsenal), and three glyphosate formulations (Roundup, Kilo Max, and Environ Glyphosate). The results showed the premetamorphic stage as the most sensitive to the herbicides toxicity. This study confirmed that the developmental stage at which amphibian are exposed to contaminants is critical to their survival and that the chemical contamination hypothesis of the global decline of amphibians should continue to be considered. This establishment of the premetamorphic larval as sensitive toxicity representative for all developmental stages of X. laevis means that this stage could be used more extensively in pesticides toxicity assessments.

The article presents a retrospective case report of a 74-year-old man that was being followed for vision changes, but whose niacin therapy was managed elsewhere. Decrease in niacin dosage resulted in resolution of retinal edema. It is concluded that there is a threshold for niacin's toxicity and that dosage decrease below the same enables continued lower dosage therapy without evident retinal adverse effects.

Terrestrial plant toxicity tests were conducted to determine the sensitivity of two boreal plants, yarrow (Achillea millefolium L.) and fireweed (Chamerion angustifolium L.), to the herbicides imazapyr and triclopyr. Both plants are common non-target species on northern powerline rights-of-way where the impacts of proposed herbicide applications are of concern. In the vegetative vigour test, triclopyr foliar spray caused extensive damage to A. millefolium at <50% of the maximum field application rate (inhibition concentration (IC) 50  = 1443.8 g a.i. ha -1 ) and was lethal to C. angustifolium at the lowest dose tested (1210.9 g a.i. ha -1 ). Both species demonstrated extremely high sensitivity to imazapyr foliar spray: IC 50s  = 8.29 g a.i. ha -1 and 4.82 g a.i. ha -1 (<1.5% of the maximum field rate). The seedling emergence and seedling growth tests were conducted in the organic horizon of five boreal soils. Few differences in herbicide bioavailability between soils were detected. Triclopyr limited growth of A. millefolium, C. angustifolium and standard test species Calamagrostis canadensis at low levels (most IC 50 estimates between 2-20 µg g -1 ). For imazapyr, IC 50 estimates could not be calculated as there was >75% inhibition of endpoints at the lowest doses of ~2 µg g -1 . A foliar application of triclopyr or imazapyr for woody species control would likely cause significant damage to boreal non-target plants. The high sensitivity of both species to herbicide residues in soil indicates long term impacts are dependent on herbicide degradation rates in northern conditions. A. millefolium performed well and is recommended for use in toxicity testing relevant to boreal regions.

Novel cytotoxins 3-5 containing the 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore are disclosed. The compounds in series 3 and 5 have the potential to liberate niacin which may reduce some of the side effects of antineoplastic compounds. 3a-c emerged as the most potent cytotoxic compounds with IC 50 values in the low micromolar range against human Molt4/C8 and CEM CD 4 + T-lymphocytes as well as murine L1210 leukemia cells. QSAR studies revealed that cytotoxic potencies were negatively correlated with the magnitude of the Hammett sigma values of the aryl substituents. The compounds 3a-e displayed tumour-selective toxicity against human HL-60, HSC-2, HSC-3 and HSC-4 neoplasms as compared to human HGF, HPC and HPLF nonmalignant cells. A representative potent compound 3a caused PARP1 cleavage and G 0 /G 1 cell cycle arrest in HSC-2 cells. These compounds are well tolerated in mice at doses up to and including 300mg/kg of the compounds and no mortalities were noted after 4h. The stability studies undertaken did not reveal that a representative compound 3a underwent hydrolysis to the related phenol 2a. Some guidelines for further analog development of the novel esters 3 were made., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Imazapyr (IMY) and imazapic (IMI) are imidazolinone herbicides which have been associated in a commercial formulation (Kifix(®)). To date, there are no studies on the toxicity of an IMY+IMI herbicide in fish. This work aimed to assess the acute toxicity (24 and 96 h) of IMY+IMI (0, 0.488 and 4.88 µg/L) towards Rhamdia quelen through hematological, biochemical, immunological, ionoregulatory and enzymatic indexes. Red blood cell count was lower at 4.88 than at 0.488 µg/L (24 and 96 h); mean corpuscular volume was lower than control at both concentrations (24 h) and at 0.488 µg/L (96 h); lymphocytes declined at 4.88 µg/L comparing to control (96 h); and monocytes increased at 4.88 µg/L (96 h) in comparison with the respective control and with 4.88 µg/L at 24h. Aspartate aminotransferase was higher at 0.488 µg/L (96 h) than the respective control and the respective concentration at 24 h; uric acid reduced at 4.88 µg/L comparing with 0.488 µg/L (96 h); and cortisol was lower at 4.88 µg/L compared to 0.488 µg/L and control (96 h). Herbicide exposure lowered plasma bactericidal activity at both concentrations (24 h) and at 0.488 µg/L (96 h); and plasma complement activity declined at 4.88 µg/L comparing with 0.488 µg/L and control (96 h), and was lower at all concentrations at 96 h than at 24 h. Plasma K(+) levels were higher at 4.88µg/L than in the remaining groups (24 and 96h); and Na(+) levels decreased at 4.88 µg/L compared to control (96 h). Na(+)/K(+)-ATPase and H(+)-ATPase activities in gills were lower at 4.88 µg/L comparing with control (24 h) and with the respective concentration at 96 h; and AChE activity in brain was higher at 0.488 and 4.88 µg/L than control (24 h) and the respective concentrations at 96 h, while in muscle it was higher at 0.488 and 4.88 µg/L than control (96 h) and the respective concentrations at 24 h. The present findings demonstrate that, despite IMY+IMI targets the animal-absent AHAS enzyme, such formulation displayed an acute toxic effect upon R. quelen homeostasis by impacting on vital functions such as immune defense, metabolism, ionoregulation and neurotransmission., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The use of lower concentrations and fewer applications of herbicides is one of the prime objectives of the sustainable agriculture as it decreases the toxicity to non-targeted organisms and the risk of wider environmental contamination. In the present work, nanoparticles were developed for encapsulation of the herbicides imazapic and imazapyr. Alginate/chitosan and chitosan/tripolyphosphate nanoparticles were manufactured, and their physicochemical stability was evaluated. Determinations were made of the encapsulation efficiency and release kinetics, and the toxicity of the nanoparticles was evaluated using cytotoxicity and genotoxicity assays. The effects of herbicides and herbicide-loaded nanoparticles on soil microorganisms were studied in detail using real-time polymerase chain reactions. The nanoparticles showed an average size of 400 nm and remained stable during 30 days of storage at ambient temperature. Satisfactory encapsulation efficiencies of between 50 and 70% were achieved for both types of particles. Cytotoxicity assays showed that the encapsulated herbicides were less toxic, compared to the free compounds, and genotoxicity was decreased. Analyses of soil microbiota revealed changes in the bacteria of the soils exposed to the different treatments. Our study proves that encapsulation of the herbicides improved their mode of action and reduced their toxicity, indicating their suitability for use in future practical applications.

Although Brazil has recently reached the position as the second largest producer of genetically modified soybean [Glycine max (L.) Merr.], there are few reports on the effects of transgenic crops and the associated use of specific herbicides on soil microbial communities, both under the edaphoclimatic conditions in Brazil, and in other producer regions in the southern hemisphere. The aim of this study was to evaluate the effects of transgenic soybean containing the ahas gene conferring resistance to herbicides of the imidazolinone group, and of the herbicides associated with transgenic soybeans on the soil microbial community. Twenty field experiments were carried out during three growing seasons (summer of 2006/2007, short-season of 2007 and summer of 2007/2008), in nine municipalities located in six Brazilian states and in the Federal District. The experiments were conducted using a completely randomized block design with four replicates and three treatments: (1) conventional (non-transgenic) soybean cultivar Conquista with conventional herbicides (bentazone + acifluorfen-sodium and other herbicides, depending on the level of infestation in each region); (2) near-isogenic transgenic Cultivance (CV127) containing the ahas gene, with conventional herbicides; (3) transgenic Cultivance with specific herbicide of the imidazolinone group (imazapyr). As the objective of the study was to verify impacts of the transgene and herbicides on the soil microbial community of the whole area and not only a punctual rhizospheric effects, samples were taken at the 0-10 cm layer prior to cropping and at R2 soybean growth stage, between plant rows. Quantitative (microbial biomass C and N, MB-C and MB-N) and qualitative (DGGE of the 16S rDNA region) parameters of soil microbial community were evaluated. No qualitative or quantitative differences were found that could be attributed to the transgene ahas. A comparison of Cultivance soybean with conventional and imidazolinone-group herbicides applications also failed to reveal differences that could be attributed to the specific use of imazapyr, even after three consecutive croppings at the same site. Finally, no differences were detected between conventional (Conquista and conventional herbicides) and transgenic soybean managements (Cultivance and imazapyr). However, marked differences were observed in MB-C and MB-N between the different sites and times of year and, for the 16S rDNA-DGGE profiles, between different sites. In conclusion, microbial community evaluations were found to be sensitive and viable for monitoring different technologies and agricultural management methods, but no differences could be attributed to the ahas transgene for three consecutive cropping seasons.

Objectives: The aim of this study was to investigate the effects of oral administration of a novel benzodiazepine derivative, JM-20, on the neurological behavior of different rodent models, focusing on the GABAergic effect. We have also investigated the acute toxicity of oral administration of JM-20 in mice., Methods: Mice or rats received oral administration of JM-20 at 2, 4, 8, and 10 mg/kg to evaluate the sedative/hypnotic, anxiolytic, and anticonvulsant effects, as well as the influence on the stereotyped behavior induced by amphetamine. Diazepam (DZP) was used as a positive control. In addition, the mice received a single oral JM-20 dose of 2000 mg/kg to evaluate the acute toxicity., Results: In a dose-dependent manner, JM-20 (i) increased the number of crossings and decreased the number of rearings in the open-field test; (ii) decreased the aggressive behavior of socially-isolated mice; and (iii) increased the latency period for tonic seizure's onset and the percentage of survival of animals with seizures. Moreover, JM-20 increased the sleeping time induced by barbiturates and the time spent and the number of entries in the open arms of the elevated plus-maze test. In the JM-20 toxicity test, no mortality was observed and only minor signs of toxicity associated with sedation were detected., Conclusions: These results indicate that JM-20 has an anxiolytic profile similar to DZP and its dihydropyridine moiety did not appear to interfere with the GABAergic activity associated with benzodiazepine. Furthermore, JM-20 did not show significant acute toxic effects in mice.

Acetohydroxyacid synthase (AHAS) catalyzes the first reaction in branch chain amino acids biosynthesis. This enzyme is the target of several herbicides, including all members of the imidazolinone family. Little is known about the expression of the three acetohydroxyacid synthase genes (ahas1, ahas2 and ahas3) in sunflower. The aim of this work was to evaluate ahas gene expression and AHAS activity in different tissues of sunflower plantlets. Three genotypes differing in imidazolinone resistance were evaluated, two of which carry an herbicide resistant-endowing mutation known as Ahasl1-1 allele. In vivo and in vitro AHAS activity and transcript levels were higher in leaves than in roots. The ahas3 transcript was the less abundant in both tissues. No significant difference was observed between ahas1 and ahas2 transcript levels of the susceptible genotype but a higher ahas1 transcript level was observed in leaves of genotypes carrying Ahasl1-1 allele. Similar transcript levels were found for ahas1 and ahas2 in roots of genotypes carrying Ahasl1-1 allele whereas higher ahas2 abundance was found in the susceptible genotype. Herbicide treatment triggered tissue-specific, gene and genotype-dependent changes in ahas gene expression. AHAS activity was highly inhibited in the susceptible genotype. Differential responses were observed between in vitro and in vivo AHAS inhibition assays. These findings enhance our understanding of AHAS expression in sunflower genotypes differing for herbicide resistance and its response to herbicide treatment., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Conflict between native amphibians and aquatic weed management in the Pacific Northwest is rarely recognized because most native stillwater-breeding amphibian species move upland during summer, when herbicide application to control weeds in aquatic habitats typically occurs. However, aquatic weed management may pose a risk for aquatic species present in wetlands through the summer, such as the Oregon spotted frog (OSF, Rana pretiosa), a state endangered species in Washington. Acute toxicity of herbicides used to control aquatic weeds tends to be low, but the direct effects of herbicide tank mixes on OSFs have remained unexamined. We exposed juvenile OSFs to tank mixes of the herbicide imazapyr, a surfactant, and a marker dye in a 96-h static-renewal test. The tank mix was chosen because of its low toxicity to fish and its effectiveness in aquatic weed control. Concentrations were those associated with low-volume (3.5 L/ha) and high-volume (7.0 L/ha) applications of imazapyr and a clean-water control. Following exposure, frogs were reared for two months in clean water to identify potential latent effects on growth. Endpoints evaluated included feeding behavior, growth, and body and liver condition indices. We recorded no mortalities and found no significant differences for any end point between the herbicide-exposed and clean-water control frogs. The results suggest that imazapyr use in wetland restoration poses a low risk of direct toxic effects on juvenile OSFs., (Copyright © 2012 SETAC.)

The anti-dyslipidemic drug niacin has recently been shown to reduce the hepatic expression and plasma levels of CETP. Since liver macrophages contribute to hepatic CETP expression, we investigated the role of macrophages in the CETP-lowering effect of niacin in mice. In vitro studies showed that niacin does not directly attenuate CETP expression in macrophages. Treatment of normolipidemic human CETP transgenic mice, fed a Western-type diet with niacin for 4 weeks, significantly reduced the hepatic cholesterol concentration (-20%), hepatic CETP gene expression (-20%), and plasma CETP mass (-30%). Concomitantly, niacin decreased the hepatic expression of CD68 (-44%) and ABCG1 (-32%), both of which are specific markers for the hepatic macrophage content. The decrease in hepatic CETP expression was significantly correlated with the reduction of hepatic macrophage markers. Furthermore, niacin attenuated atherogenic diet-induced inflammation in liver, as evident from decreased expression of TNF-alpha (-43%). Niacin similarly decreased the macrophage markers and absolute macrophage content in hyperlipidemic APOE*3-Leiden.CETP transgenic mice on a Western-type diet. In conclusion, niacin decreases hepatic CETP expression and plasma CETP mass by attenuating liver inflammation and macrophage content in response to its primary lipid-lowering effect, rather than by attenuating the macrophage CETP expression level., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Lange's metalmark butterfly, Apodemia mormo langei Comstock, is in danger of extinction due to loss of habitat caused by invasive exotic plants which are eliminating its food, naked stem buckwheat. Herbicides are being used to remove invasive weeds from the dunes; however, little is known about the potential effects of herbicides on butterflies. To address this concern we evaluated potential toxic effects of three herbicides on Behr's metalmark, a close relative of Lange's metalmark. First instars were exposed to recommended field rates of triclopyr, sethoxydim, and imazapyr. Life history parameters were recorded after exposure. These herbicides reduced the number of adults that emerged from pupation (24-36%). Each herbicide has a different mode of action. Therefore, we speculate that effects are due to inert ingredients or indirect effects on food plant quality. If these herbicides act the same in A. mormo langei, they may contribute to the decline of this species., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Nicotinic acid was grafted on (poly(ɛ-caprolactone))(2)-poly(ethylene glycol) copolymers that were used for the preparation of nanoparticles with the objectives to monitor particle size and to optimize the drug loading capacity as well as the release profile of the particles. Increasing amounts of grafting nicotinic acid increased the particle size as a result of an enhanced hydrophobicity of the copolymer. Ibuprofen and indomethacin with two different molecular characteristics were selected as model drugs to be bound to the nanoparticles. The presence of grafting nicotinic acid enhanced the loading capacity for both drugs compared to the nanoparticles without nicotinic acid. However, no correlation between amount of grafting nicotinic acid and loading capacity was observed. The release characteristic of both drugs was fitted to the Higuchi model indicating Fickian diffusion. The release characteristic of indomethacin mainly depended on the crystalline property of the copolymer whereas that of ibuprofen was additionally influenced by the hydrogen bonding between drug and grafted copolymer., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The use of niacin to improve plasma lipid levels and reduce risk of myocardial infarction is limited by noxious skin effects that result from stimulation of G protein-coupled receptor 109A (GPR109A) in skin immune cells. Niacin causes vasodilation, manifest as rubor (redness) of the head and neck, providing a visible sign associated with other, more bothersome skin complaints. The working theory is that niacin provokes Langerhans cells to produce prostaglandin D2 (PGD2), stimulating vascular DP1 receptors to cause vasodilation. In this issue of the JCI, Hanson and colleagues raise a serious challenge to this paradigm in showing that the major player in vasodilation is the keratinocyte, which produces PGE2, stimulating EP2/4 receptors, shifting the role of the Langerhans/PGD2/DP1 pathway to that of an accomplice. They also show that the antipsoriasis drug monomethyl fumarate, itself a GPR109A agonist, provokes vasodilation through the same cells. These efforts bring us one step closer to solving a key limitation of an important cardioprotective drug and reveal that the skin response to niacin is much more complicated than previously thought.

The antidyslipidemic drug nicotinic acid and the antipsoriatic drug monomethyl fumarate induce cutaneous flushing through activation of G protein-coupled receptor 109A (GPR109A). Flushing is a troublesome side effect of nicotinic acid, but may be a direct reflection of the wanted effects of monomethyl fumarate. Here we analyzed the mechanisms underlying GPR109A-mediated flushing and show that both Langerhans cells and keratinocytes express GPR109A in mice. Using cell ablation approaches and transgenic cell type-specific GPR109A expression in Gpr109a-/- mice, we have provided evidence that the early phase of flushing depends on GPR109A expressed on Langerhans cells, whereas the late phase is mediated by GPR109A expressed on keratinocytes. Interestingly, the first phase of flushing was blocked by a selective cyclooxygenase-1 (COX-1) inhibitor, and the late phase was sensitive to a selective COX-2 inhibitor. Both monomethyl fumarate and nicotinic acid induced PGE2 formation in isolated keratinocytes through activation of GPR109A and COX-2. Thus, the early and late phases of the GPR109A-mediated cutaneous flushing reaction involve different epidermal cell types and prostanoid-forming enzymes. These data will help to guide new efficient approaches to mitigate nicotinic acid-induced flushing and may help to exploit the potential antipsoriatic effects of GPR109A agonists in the skin.

The objective of this study was to evaluate the effects of a novel oxygen-coordinated niacin-bound chromium(III) complex (NBC) on the reproductive systems of male and female rats, the postnatal maturation and reproductive capacity of their offspring, and possible cumulative effects through multiple generations. Sprague-Dawley rats were maintained on feed containing NBC at dose levels of 0, 4, 15, or 60ppm for 10weeks prior to mating, during mating, and, for females through gestation and lactation, across two generations. For the parents (F(0) and F(1)) and the offspring (F(1) and F(2a)), reproductive parameters such as fertility and mating, gestation, parturition, litters, lactation, sexual maturity and development of offspring were assessed. Results from the current study indicated that dietary exposure of NBC to parental male and female rats of both (F(0) and F(1)) the generations during the premating and mating periods, for both sexes, and during gestation and lactation in case of female rats, did not cause any significant incidence of mortality or abnormal clinical signs. Compared to respective controls, NBC exposure did not affect reproductive performance as evaluated by sexual maturity, fertility and mating, gestation, parturition, litter properties, lactation and development of the offspring. Based on the findings of this study, the parental as well as the offspring no-observed-adverse-effect level for NBC was determined to be greater than 60ppm in diet or equivalent to 7.80 and 8.31mg/kg body weight/day in male and female rats, respectively.

The objective of the present study was to evaluate the teratogenic potential of a novel oxygen-coordinated niacin-bound chromium complex (NBC) in Sprague-Dawley rats. Due to its potential to affect fat synthesis and reduce food intake, processes which are often crucial in normal fetal development, this teratology study was undertaken as part of a multi-generation reproductive investigation. The animals in this study were selected randomly after weaning from each F(2b) litter of the F1 generation from the two-generation reproductive toxicity study. To start the teratology study, Sprague-Dawley rat pups ( approximately 30/sex/group) from the F(2b) generation were allowed to grow up to 10-12 weeks of age before mating. The rats in treatment group were exposed directly to NBC through feed. The dietary exposure levels were the same as those employed for the two-generation reproductive toxicity study, viz. 4, 15, or 60 ppm. Following mating at maturity, the pregnant rats were observed daily for clinical signs of adverse effects, and body weight and feed consumption were recorded. On the day 20th of the gestation, animals were subjected to a necropsy and caesarean section to examine the uterus, ovaries and fetuses for assessment of different parameters of pregnancy and embryo-fetal defects. In this study, no indications of maternal toxicity, adverse effects on the parameters evaluated for the gravid uteri, external abnormalities in the fetuses, soft tissue abnormalities in the fetuses, or skeletal abnormalities in the fetuses were noted. Based on the results of this developmental toxicity study, NBC was found to benon-teratogenic in Sprague-Dawley rat, at the dietary exposure levels of 4, 15, and 60 ppm, equivalent to the dose levels of 0.50, 2.0, or 8.0mg/kg/day, respectively.

To determine the tolerable upper intake level of nicotinic acid in humans, we investigated the effects of excess nicotinic acid administration on body weight gain, food intake, and urinary excretion of water-soluble vitamins and the metabolism of tryptophan in weaning rats. The weaning rats were freely fed a niacin-free 20% casein diet (control diet) or the same diet with 0.1%, 0.3% or 0.5% nicotinic acid for 23 days. The excess nicotinic acid intake did not affect body weight gain, food intake, serotonin contents in the brain, stomach and small intestine, or the urinary excretions of water-soluble vitamins. Although excess nicotinic acid did not affect the upper part of the tryptophan-nicotinamide pathway, 0.5% nicotinic acid diet increased the urinary excretion of quinolinic acid. The diet containing more than 0.3% nicotinic acid also increased the urinary excretion of nicotinic acid, which is usually below the limit of detection. As determined from the results of body weight gain and food intake as indices for apparent adverse effects, the no-observed-adverse-effect-level (NOAEL) for nicotinic acid was 0.5% in diet, corresponding to 450 mg/kg body weight/day. As judged from in increase of urinary quinolinic acid and nicotinic acid as indices of metabolic change, NOAEL was 0.1% in diet, corresponding to 90 mg/kg body weight/day, and the lowest-observed-adverse-effect-level (LOAEL) was 0.3% in diet, corresponding to 270 mg/kg body weight/day.

Background, Aim, and Scope: Large-scale deforestation is occurring in subarctic North America following clearing by salvage logging or insect attack. Numerous shrubs, herbs, and deciduous tree species tend to dominate areas on which stands of white spruce have grown. In the absence of economically advantageous mechanical methods, several herbicides have value in efforts to reforest by planting white spruce. Glyphosate, imazapyr, triclopyr, and hexazinone are all capable of selectively removing many competing species, but there is concern about whether they would degrade naturally or persist owing to the frigid climate., Materials and Methods: We established test plots with all four herbicides in upland and river bottom sites at 65 degrees N and 58 degrees N latitudes. The northern site has extremely cold winters, with soils that freeze to a depth of 1-2 m, and precipitation of 275 mm/year. The southern site has heavy rain and snowfall, amounting to 2,250 mm/year evenly distributed. Soil seldom freezes deeply. On each test plot, one of the four herbicides was applied at twice the normal operational use rate to facilitate detection. They were applied at the normal timing, with hexazinone, imazapyr, and triclopyr applied in June and glyphosate applied in fall. Soils were sampled immediately after treatment and those samples used as references for dissipation data gathered over the next 11-14 months from soil 0- to 15- and 15- to 45-cm depths., Results: Dissipation rates did not follow first-order rates because freezing conditions slowed most microbial activity. All products dissipated to close to or below detection limits within the time of the study. Dissipation from vegetation was substantially more rapid and depended on the nature of the plants treated as well as the product used. While soil residues dissipated more slowly than in temperate regions, they did display consistent dissipation patterns during above-freezing conditions and also the influence of microbial activity. Mobility was very limited with all products but hexazinone., Discussion: These products dissipate during summer in high latitudes much as they would in temperate climates. Winter changes are small, but are not unlike some changes reported elsewhere under freezing conditions. Unlike many other studies, soil water did not influence dissipation heavily, but the high latitude and semi-arid climate also did not create severely droughty soils. Residues in plants were much higher than those in soils, but denatured the vegetation quickly, leading to unsuitability for forage in any case., Conclusions: Low toxicity of these products and their metabolites combined with consistent dissipation and low mobility suggest that toxic hazard of their use at high latitudes need not be a matter of serious concern to humans, terrestrial wildlife, or aquatic systems. They are safe for use in management and rehabilitation of boreal forests when used properly., Recommendations and Perspectives: Dissipation at rates approaching those in warmer climates offer a hypothesis that microflora native to high latitudes may be adapted to destruction of such molecules at lower temperatures than may be indicated by experiments with microflora adapted to warmer climates. Residues pose no observable risk to wildlife or humans in the area of use when products are applied properly.

Thiazopyr increases the incidence of male rat thyroid follicular-cell tumors; however, it is not carcinogenic in mice. Thiazopyr is not genotoxic. Thiazopyr exerts its carcinogenic effect on the rat thyroid gland secondary to enhanced metabolism of thyroxin leading to hormone imbalance. The relevance of these rat tumors to human health was assessed by using the 2006 IPCS Human Relevance Framework. The postulated rodent tumor mode of action was tested against the Bradford Hill criteria and was found to satisfy the conditions of dose and temporal concordance, biological plausibility, coherence, strength, consistency, and specificity that fits with a well-established mode of action for thyroid follicular-cell tumors. Although the postulated mode of action could theoretically operate in humans, marked quantitative differences in the inherent susceptibility for neoplasia to thyroid hormone imbalance in rats allows for the conclusion that thiazopyr does not pose a carcinogenic hazard to humans.

We investigated the effects of a combined treatment with chromium (Cr) and niacin on the spleen, tongue, and lens tissues in terms of lipid peroxidation (LPO), glutathione (GSH), serum catalase (CAT), lactate dehydrogenase (LDH), serum cholesterol, and total lipid levels in normal and hyperlipemic rats. In this study, female 1-year-old Swiss albino rats were used. The rats were randomly divided into four groups. Group I rats (control) were fed with standard pellet chow. Group II rats were fed a lipogenic diet in which 2% cholesterol, 0.5% cholic acid, and 20% sunflower oil were added and were given 3% alcoholic water for 60 days. Group III rats were fed with the same lipogenic diet and were treated with a dose of 250 microg/kg body weight CrCI3 x 6H2O and 100 mg/kg body weight niacin, for 45 days, by gavage. The rats in group IV were fed with pellet chow and treated with 250 microg/kg body weight CrCI3 x 6H2O and 100 mg/kg body weight niacin, by gavage, for 45 days. After 2 weeks, the animals showed symptoms of hyperlipemia. On the 60th day, tissue and blood samples were taken. We have observed decreased CAT activity and GSH levels, increased LDH activity, cholesterol, total lipid, and LPO levels in hyperlipemic rats. Niacin and Cr administration to hyperlipemic rats increased tissue GSH levels and CAT activity and decreased tissue LPO levels and LDH activity, cholesterol, and total lipid levels compared with hyperlipemic rats. We conclude that the administration of a combination of niacin and chromium has a protective effect against oxidative damage to tongue, lens, and spleen tissues as a result of hyperlipemia.

Chromium is an essential trace element required for normal protein, fat and carbohydrate metabolism. It also helps in energy production and increasing lean body mass. Niacin-bound chromium (NBC) is a unique form of bioavailable chromium that promotes healthy lipid profile. This study was focused on determining the broad spectrum safety of NBC. Acute oral, acute dermal, primary dermal irritation and primary eye irritation toxicities of NBC were evaluated. Ames bacterial reverse mutation assay, mouse lymphoma test and a dose-dependent 90-day subchronic toxicity were also conducted. In safety studies, the acute oral LD(50) of NBC was found to be greater then 5000 mg/kg in both male and female Sprague-Dawley rats. No changes in body weight or adverse effects were observed following necropsy. The acute dermal LD(50) of NBC was found to be >2000 mg/kg. The primary skin irritation test was conducted with NBC on New Zealand Albino rabbits. NBC was classified as slightly irritating. The primary eye irritation test was conducted with NBC on rabbits. NBC was classified as practically non-irritating to the eye. NBC did not induce mutagenic effects in the bacterial reverse mutation test in five Salmonella typhimurium strains (TA1535, TA98, TA100, TA97a and TA102), either with or without metabolic activation. Similarly, NBC did not induce mutagenic effects in the mammalian cell gene mutation test in L5178Y mouse lymphoma cells TK (+/-), either with or without metabolic activation. A dose-dependent 90-day subchronic toxicity study demonstrated no significant changes in selected organ weights individually and as percentages of body and brain weights. NBC supplementation did not cause changes in hepatic lipid peroxidation or DNA fragmentation after 30, 60 or 90 days of treatment. Hematology, clinical chemistry and histopathological evaluations did not show any adverse effects in all organs tested. Taken together, the above results indicate a broad spectrum of safety for NBC.

A large scale ecosystem restoration program was initiated in 1997 on the Pecos River in Western Texas. Saltcedar (Tamarix spp.), a non-native invasive tree, had created a near monoculture along the banks of the river by replacing most native vegetation. Local irrigation districts, private landowners, federal and state agencies, and private industry worked together to formulate and implement a restoration plan, with a goal of reducing the effects of saltcedar and restoring the native ecosystem of the river. An initial management phase utilizing state-of-the-art aerial application of herbicide began in 1999 and continued through 2003. Initial mortality of saltcedar averaged about 85-90%. Monitoring efforts were initiated at the onset of the project to include evaluating the effects of saltcedar control on salinity of the river water, efficiency of water delivery down the river as an irrigation water source, and estimates of water salvage. To date, no effect on salinity can be measured and irrigation delivery was suspended in 2002-2003 due to drought conditions. Water salvage estimates show a significant reduction in system water loss after saltcedar treatment. However, a flow increase in the river is not yet evident. Monitoring efforts will continue in subsequent years.

Niacinamide (aka nicotinamide) and Niacin (aka nicotinic acid) are heterocyclic aromatic compounds which function in cosmetics primarily as hair and skin conditioning agents. Niacinamide is used in around 30 cosmetic formulations including shampoos, hair tonics, skin moisturizers, and cleansing formulations. Niacin is used in a few similar product types. The concentration of use of Niacinamide varies from a low of 0.0001% in night preparations to a high of 3% in body and hand creams, lotions, powders and sprays. Niacin concentrations of use range from 0.01% in body and hand creams, lotions, powders and sprays to 0.1% in paste masks (mud packs). Both ingredients are accepted for use in cosmetics in Japan and the European Union. Both are GRAS direct food additives and nutrient and/or dietary supplements. Niacinamide may be used in clinical treatment of hypercholesteremia and Niacin in prevention of pellegra and treatment of certain psychological disorders. Both ingredients are readily absorbed from skin, blood, and the intestines and widely distribute throughout the body. Metabolites include N1-methylnicotinamide and N1-methyl-4-pyridone-3-carboxamide. Excretion is primarily through the urinary tract. While Niacinamide is more toxic than Niacin in acute toxicity studies, both are relatively non-toxic. Short-term oral, parenteral, or dermal toxicity studies did not identify significant irreversible effects. Niacinamide, evaluated in an in vitro test to predict ocular irritation, was not an acute ocular hazard. Animal testing of Niacinamide in rabbits in actual formulations produced mostly non-irritant reactions, with only some marginally irritating responses. Skin irritation tests of up to 2.5% Niacinamide in rabbits produced only marginal irritation. Skin sensitization tests of Niacinamide at 5% during induction and 20% during challenge were negative in guinea pigs. Neither cosmetic ingredient was mutagenic in Ames tests, with or without metabolic activation. Niacinamide and Niacin at 2 mg/ml were negative in a chromosome aberration test in Chinese hamster ovary cells, but did produce large structural chromosome aberrations at 3 mg/ml. Niacinamide induced sister chromatid exchanges in Chinese hamster ovary cells, but Niacin did not. Under certain circumstances, Niacinamide can cause an increase in unscheduled DNA synthesis in human lymphocytes treated with UV or a nitrosoguanidine compound. Niacinamide itself was not carcinogenic when administered (1%) in the drinking water of mice. No data on the carcinogenic effect of Niacin were available. Niacinamide can moderate the induction of tumors by established carcinogens. Niacinamide in combination with streptozotocin (a nitrosourea compound) or with heliotrine (a pyrrolizidine alkaloid), produced pancreatic islet tumors. On the other hand, Niacinamide reduced the renal adenomas produced by streptozotocin; and intestinal and bladder tumors induced by a preparation of bracken fern. Niacinamide evaluated in in vitro test systems did affect development, but Niacinamide reduced the reproductive/developmental toxicity of 2-aminonicotinamide-amino-1,3,4-thiadiazole hydrochloride and urethane. Clinical testing of Niacinamide produced no stinging sensation at concentrations up to 10%, use tests produced no irritation at concentrations up to 5%, and a 21-day cumulative irritation test at concentrations up to 5% resulted in no irritancy. Niacinamide was not a sensitizer, nor was it a photosensitizer. The CIR Expert Panel considered that Niacinamide and Niacin are sufficiently similar from a toxicologic standpoint to combine the available data and reach a conclusion on the safety of both as cosmetic ingredients. Overall, these ingredients are non-toxic at levels considerably higher than would be experienced in cosmetic products. Clinical testing confirms that these ingredients are not significant skin irritants, sensitizers or photosensitizers. While certain formulations were marginal to slight ocular irritants, other formulations were not. Niacinamide, while not carcinogenic alone, can modulate the induction of tumors by certain established carcinogens. The Panel noted that the doses in these studies are high relative to the low concentrations at which Niacinamide is used in cosmetic formulations. In neither case (tumor protection or tumor promotion) are these findings considered relevant to the use of Niacinamide at its current low concentrations of use in cosmetics. Both ingredients were considered safe as used in cosmetics.

The herbicide arsenal 250 NA, its technical-grade active ingredient imazapyr, and the surfactant nonylphenol ethoxylate (NP) were evaluated through genotoxicity and toxicity studies in different organisms. A comparative study of these three compounds was carried out to assess how the addition of surfactant components may pose the highest toxicological risk to pesticide formulations. The results showed that arsenal, imazapyr, and NP did not cause chromosome aberration in Allium cepa nor increase the frequency of micronuclei in mice. However, toxicological evaluations showed that NP was the most toxic compound to mice, A. cepa, Drosophila melanogaster, and Biomphalaria tenagophila. In this evaluation, it was observed that the adverse effects were produced by the surfactant additive of the pesticide formulation., (Copyright 2004 Elsevier Inc.)

Background: A series of isolated studies has focused on the influence of smoking on bone around titanium implants. This study proposes to investigate the impact of two conditions, i.e., nicotine administration and cigarette smoke inhalation, on the healing around implants., Methods: Forty-five Wistar rats were used. After anesthesia, the tibiae surface was exposed and a screw-shaped titanium implant was placed bilaterally. The animals were randomly assigned to one of the following groups: Group 1: control, n = 19; Group 2: intermittent cigarette smoke inhalation, n = 15; and Group 3: subcutaneous administration of nicotine (3 mg/kg) twice daily, n = 11. After 60 days, the animals were sacrificed. The degree of bone-to-implant contact (BIC) and the bone area (BA) within the limits of the threads of the implant were measured in the cortical (zone A) and cancellous bone (zone B) areas., Results: In zone A, cigarette smoke presented a significant negative influence on BIC and BA (Kruskal-Wallis test, P < 0.05). In contrast, the administration of nicotine did not influence either parameter (P > 0.05). In zone B, cigarette smoke inhalation also resulted in a decreased percentage of BIC compared to the control group (P < 0.05). In addition, the BA was significantly decreased in groups 2 and 3 when compared to controls (P > 0.05)., Conclusion: The negative impact of smoking on implant outcomes may be related to more than one molecule present in the cigarette smoke and nicotine seems to partially contribute, especially in the cancellous bone.

Increased herbicide use in silviculture over the last several decades has led to concern over potential water contamination, which may affect biotic health. In the southeastern United States, pine flatwoods are important for timber production and are often interspersed with cypress wetlands. Cypress domes are isolated, shallow basins that collect surficial waters from adjacent forested areas and therefore might be expected to contain pesticide from storm runoff. This study utilizes in situ microcosm experiments to assess the effects of a concentration gradient of the herbicide imazapyr (0.184, 1.84, and 18.4 mg/L, equivalent to 1, 10, and 100 times the expected environmental concentration from a normal application rate) on the macroinvertebrate community of a logged pond cypress dome using changes in macroinvertebrate composition, chironomid biomass, and chironomid head-capsule deformities. The control core was not significantly different from the surrounding cypress dome for any parameter, suggesting that enclosure effects were likely of minimal importance in the final experimental results. The lack of statistical difference (p < 0.05) in macroinvertebrate community composition, chironomid deformity rate, and chironomid biomass between treatments suggests that imazapyr did not affect the macroinvertebrate community at the concentrations tested. Chironomid deformity rate ranged from 0.97% for imazapyr control to 4.96% for the 100x treatment, with chironomid biomass being 1.79 and 1.87 mg/L, respectively.

Parasitic Orobanche spp are major constraints to vegetable crop production in the Mediterranean basin (to eastern Europe) and in localized places in India, China and the USA. Transgenic target-site herbicide resistance (eg, to acetolactate synthase inhibitors) allows for movement of unmetabolized herbicide through the crop to the photosynthate sink in the parasite, as well as through the soil. We report the successful engineering of a mutant acetolactate synthase (ALS) gene into carrot, allowing control of broomrape already in heterozygotes of the first back-crossed generation, by imazapyr, an imidazolinone ALS inhibitor. It is expected that homozygotes will have higher levels of resistance.

Raphanus raphanistrum L has evolved widespread resistance to sulfonylureas in the Western Australia (WA) wheat belt. With the introduction of imidazolinone-tolerant (IT) wheat (Tritcum aestivum L) and IT canola (Brassica napus L) in the WA wheat belt, it is important to understand the status of cross-resistance in this weed to sulfonylurea and imidazolinone (Imi) herbicides. A study was conducted to examine cross-resistance between chlorsulfuron and Imi herbicides (a mixture of imazapic and imazapyr) in 46 R raphanistrum populations collected from across the WA wheat belt. Plants were treated with herbicides and assessed for phytotoxicity under glasshouse conditions. Of the 46 R raphanistrum populations, 32 were resistant to chlorsulfuron and four were resistant to imazapic + imazapyr. Of the 70% chlorsulfuron-resistant populations, 13% showed cross-resistance to imazapic + imazapyr. However, the cross-resistant populations treated with imazapic + imazapyr showed a lower resistance level than the chlorsulfuron-treated populations. These results suggest that weed populations with such cross-resistance will not be controlled effectively by Imi herbicides. Although the resistance levels of the cross-resistant populations to Imi herbicides were low, the cross-resistance levels of R raphanistrum should be determined before growing IT crops, particularly IT canola.

The effects of nicotinic acid (2500 mg orally during 12 hr) and pyridoxine (300 mg orally twice daily for seven days) on the excretion of urinary 2,3-dinor-6-ketoprostaglandin F1alpha, 11-dehydrothromboxane B2 and leukotriene E4, the markers of systemic prostacyclin, thromboxane A2 and cysteinyl leukotriene production, respectively, were investigated in healthy male volunteers (n=6-8). Nicotinic acid increased 11-dehydrothromboxane B2 and leukotriene E4 excretions to 2.6- and 2.0 times the initial values (P<0.05), respectively. In the volunteers treated with pyridoxine, 11-dehydrothromboxane B2 and leukotriene E4 excretions were decreased to 70% (P<0.05) and 65% (P<0.01) of the initial values, respectively, but the excretion of 2,3-dinor-6-ketoprostaglandin F1alpha was increased 1.7 times (P<0.01). The results suggest that nicotinic acid increases thromboxane and leukotriene synthesis which may not be beneficial for patients with cardiovascular diseases or asthma. In contrast, the increase in prostacyclin production and the inhibition in thromboxane and leukotriene synthesis by pyridoxine might be beneficial in disorders where the production of prostacyclin is decreased and the formation of thromboxane and cysteinyl leukotrienes is enhanced.

Niacin (nicotinic acid) in its non-physiological dose level is known to be an effective lipid-lowering agent; its potential risk as a therapeutic agent, however, has not been critically considered. Since niacin is excreted predominantly as methylated pyridones, requiring methionine as a methyl donor, the present study was undertaken to examine whether metabolism of the amino acid is altered in the presence of large doses of niacin. Male Sprague-Dawley rats were given a nutritionally adequate, semi-synthetic diet containing niacin at a level of either 400 or 1000mg/kg diet (compared to 30mg/kg in the control diet) for up to 3 months. Supplementation with niacin (1,000 mg/kg diet) for 3 months resulted in a significant increase in plasma and urinary total homocysteine levels; this increase was further accentuated in the presence of a high methionine diet. The hyperhomocysteineaemia was accompanied by a significant decrease in plasma concentrations of vitamins B6 and B12, which are cofactors for the metabolism of homocysteine. The homocysteine-raising action of niacin, in particular, has an important toxicological implication, as hyperhomocysteineaemia is considered to be an independent risk factor for arterial occlusive disease. The niacin-associated change in homocysteine status may be an important limiting factor in the use of this vitamin as a lipid-lowering agent.

Niacin favorably alters all major lipid subfractions at pharmacologic doses. Alone or in combination, it promotes regression of coronary artery disease, decreases coronary events, stroke, and total mortality. Major recent progress in niacin is in four areas. Firstly, recent data indicate that it increases high-density lipoprotein (HDL) and lowers triglycerides and low-density lipoprotein (LDL) by mechanisms different from statins, fibrates, and bile-sequestrants, giving rationale for combination therapy to achieve synergistic effects for complete lipid goal achievement. Secondly, new data on an extended-release preparation of niacin given once nightly indicates that it is as effective and has greater tolerability than immediate-release niacin. Thirdly, preliminary data with a single tablet formulation extended-release niacin and an HMG CoA reductase inhibitor (lovastatin) shows it to be safe and very effective, especially for raising HDL. Finally, emerging evidence indicates that niacin can be used effectively and safely in patients with type 2 diabetes mellitus, who often have low HDL levels.

Chronic administration of thiazopyr in the diet at dose levels of 1000 and 3000 ppm, but not 100 ppm, has demonstrated an increase in thyroid follicular cell tumors in male Sprague-Dawley rats. In the studies reported here we have evaluated the mechanism of thiazopyr-induced thyroid tumors by studying the effect of thiazopyr on a number of endpoints that indicate hypothalamic-pituitary-thyroid homeostasis. At a dose level of 3000 ppm, thiazopyr caused a marked depression in circulating levels of T4 as soon as 7 days after commencement of treatment. Concurrent with this decrease in T4 was an increase in TSH levels, an increase in thyroid and liver weights, a three- to sixfold increase in hepatic T4-uridine diphosphate glucuronosyl transferase (UDPGT) activity, and increases in thyroid follicular cell hypertrophy and hyperplasia. Dose-related changes associated with thiazopyr treatment were significant increases in liver weight, thyroid weight, and hepatic T4-UDPGT activity at high doses. Increased levels of serum TSH, T3, and rT3, decreased levels of T4, and an increased incidence of thyroid follicular cell hypertrophy and hyperplasia were observed 56 days after the initiation of 3000 ppm thiazopyr. All the changes, except thyroid weight, were partially or completely reversible upon removal of thiazopyr from the diet. Increased thyroid T4 elimination, primarily via increased hepatic conjugation by T4-UDPGT, resulting in decreased serum T4, appeared to be responsible for the increased TSH levels. The sustained increase in TSH by thiazopyr appears responsible for the stimulation of the thyroid follicular cells resulting in follicular cell hypertrophy, hyperplasia, and ultimately neoplasia. In summary, evidence is presented for a hormonally mediated, threshold-dependent process for the development of thyroid follicular cell tumors from high-dose thiazopyr administration in male rats. This mechanism is not considered to be relevant to humans, since the thyroid of humans is much less sensitive to this pathogenic phenomenon than rodents.

The influence of the chemico-physical nature of the vehicle on the skin penetration of topically applied drugs was evaluated in vivo. Five different ointment formulations containing nicotinate esters as model penetrants were tested on human skin. The degree of drug penetration allowed by the various formulations was revealed by means of the erythema induced by the drug, detected by a X-Rite tristimulus reflection colorimeter. The excipient influenced the penetration of the nicotinate esters used to various extents. The concentrations of the tested drugs were found to be an important factor influencing drug penetration and persistence of erythema.

Tibia dimensions and mechanical properties were determined in White Leghorn cockerels that had been fed from 0.1 to 2.0% niacin as a supplement to standard poultry diets. Four experiments of from 20 to 38 days were conducted. No significant differences due to niacin were found in weight gain, feed consumed or feed:gain ratios. Decreases in the exterior (P < 0.009) and interior (P < 0.015) diameters of the major axes of the tibiae were found at 0.75-2.0% niacin. Exterior (P < 0.005) and interior (P < 0.001) diameters of the minor axes of the tibia were decreased at levels of 0.75 and 1%. Changes occurred in lateral wall thickness of chicks fed 0.75% niacin for 20 days (P < 0.004) and 38 days (P < 0.023) and in anterior wall thickness of 6-month-old chickens fed 1.0% niacin for 28 days (P < 0.001). Ultimate force was decreased in young chicks fed 1.0 and 1.5% niacin (P < 0.014) and 6-month-old White Leghorn chickens fed 1.0% niacin (P < 0.004). The addition of high levels of niacin to chick rations resulted in changes in dimensions, bone strength and susceptibility to fracture.

The presence of nicotine acid in the dustgaseous pollution from biochemical plants producing fodder yeast has been shown. Its allergic and sensitizing role compared to the same properties of protein-containing dust has been pointed out. It has been suggested that MAC of nicotine acid should be established for the sanitary-protective zone of microbiological industry enterprises.

Chemicals such as PB, DDT, EED, sodium deoxycholate, thiobenzamide, orotic acid and SorFAE which enhance the formation of liver tumors or HN, caused a marked decrease in PK activity in Wistar rat liver that persisted for at least 4 weeks, though the decrease caused by EED was not so marked as that caused by other hepatic promoters. Non-promoting agents such as DH, and some chemicals, such as DEXA, testosterone and AB, which enhance the formation of GGT-positive foci in rat livers, but do not enhance the formation of tumors or HN, caused decreases in PK activity in some cases. Any such decreases, however, were only transient and normal levels were restored within 4 weeks. The results suggest that the continuous decrease in PK activity may be a useful marker in screening tests for the promoters of hepatocarcinogenesis.

Nicotinic acid is used widely in the treatment of hyperlipoproteinemias and reduces both the cholesterol and the triglyceride concentrations in the plasma. However, very high doses are needed to achieve these therapeutic effects, which is why side effects are common and are particularly known to hinder the compliance of patients. Nicotinic acid derivatives have been developed to overcome this problem. As a result of chemical and galenic retardation, these derivatives lessen the side effects and the necessary doses are considerably reduced in comparison with pure nicotinic acid. However, most of these derivatives are not pure prodrugs, and exert their own synergistic pharmacokinetic and pharmacodynamic effects. In general, when nicotinic acid and its derivatives are used in therapy a desirable modification of the composition of the plasma lipids in the sense of an antiatherosclerotic activity can be expected (reductions of VLDL and LDL and an increase of HDL). Good possibilities for using nicotinic acid in the prevention and remission of atherosclerotic processes arise in connection with the activation of fibrinolysis and the reduction of the tendency toward platelet aggregation. In the light of recent studies on the mechanisms of action of nicotinic acid, an influence on the prostaglandin system has been found, as a result of which an interconnection between its various effects and side effects appears to be possible.