Hepatic metabolism, phase I and II biotransformation enzymes in Atlantic salmon (Salmo Salar, L) during a 12 week feeding period with graded levels of the synthetic antioxidant, ethoxyquin.

The synthetic antioxidant ethoxyquin (EQ) is a widely used additive in animal feeds, including farmed fish feed. The use of EQ as food additive is prohibited and it is also undesirable in farmed meat and fish products. The possible negative aspects of EQ in fish feeds, such as modulation of hepatic detoxifying enzymes and possible effects through "carry-over" to edible parts of fish are not known. In addition, the subsequent consequences for human consumers have not been previously studied. In the present work, the alteration in gene and protein expression patterns, and catalytic activities of phase I and II hepatic biotransformation enzymes due to prolonged exposure to graded levels of dietary EQ in the range of 11-1800 mg EQ/kg feed were studied. The kinetics of parent EQ and its major metabolite, ethoxyquin dimer (EQDM) was also studied. In general two weeks seem to be the critical point in the entire toxicological response of salmon to dietary consumed EQ. Biotransformation of EQ to EQDM is shown to be a rapid process. However, the decrease in biotransformation rate results in the accumulation of EQ metabolites, high concentration of which was postulated to alter translation and post-translational modification of CYP3A, GST and UDPGT at feeding day 14 and 42, with subsequent decreases in the biotransformation of consumed EQ. Decrease in the biotransformation of consumed EQ produced the retention of un-metabolized EQ rather than metabolites in salmon liver. This may be considered as undesirable effect, since it could lead to the transport and accumulation in other organs and edible tissues. It may also cause a new wave of biotransformation with formation of metabolites inhibiting detoxifying enzymes. In general, these processes may prolong the excretion of dietary EQ from the fish body and produce EQ-derived residues in the ready-to-consume salmon or fish products. These EQ residues may have higher toxicological effects for human consumers than the parent compound and therefore need to be studied in more detail.     

Hepatic biotransformation and metabolite profile during a 2-week depuration period in Atlantic salmon fed graded levels of the synthetic antioxidant, ethoxyquin.

The synthetic antioxidant ethoxyquin (EQ) is increasingly used in animal feeds and has been candidate for carcinogenicity testing. EQ has the potential for toxicological and adverse health effects for both fish and fish consumers through "carryover" processes. The toxicological aspects of EQ have not been systematically investigated. The present study was performed to investigate the hepatic metabolism, metabolite characterization, and toxicological aspects of EQ in salmon during a 2-week depuration after a 12-week feeding period with 18 mg (low), 107 mg (medium), and 1800 mg/kg feed (high). The alteration in gene expressions and catalytic activities of hepatic biotransformation enzymes were studied using real-time polymerase chain reaction with specific primer pairs and by kinetics of two identified hepatic metabolites. Analysis of EQ metabolism was performed using high performance liquid chromatography (HPLC) method and showed the detection of four compounds of which two were quantified, parent EQ and EQ dimer (EQDM). Two metabolites were identified as de-ethylated EQ (DEQ) and quinone imine, but these were not quantified. The concentration of the quantified EQ-related compounds in the liver at day 0 showed a positive linear relationship with measured dietary EQ (R2= 0.86 and 0.92 for parent EQ and EQDM, respectively). While the low-EQ-feeding group showed a time-specific increase of aryl hydrocarbon receptor (AhR) mRNA expression, the medium-dose group showed decreased AhR mRNA at depuration day 7. Expression of CYP1A1 was decreased during the depuration period. Consumption of dietary EQ produced the expression of CYP3A, glutathione S-transferase (GST), and uridine diphosphate glucuronosyl-transferase (UDPGT) mRNA during the depuration period. A similar pattern of effect was observed for both CYP3A and phase II genes and supports our previous postulation of common regulation of these enzymes by the same inducer, namely EQ metabolites. The increase of CYP3A, UDPGT, and GST gene expressions at day 7 was in accordance with the low concentration of DEQ. The low concentration of putative DEQ may induce the CYP3A with subsequent increase in the biotransformation of EQ into DEQ. The increase in UDPGT may seem to be a synchronizing mechanism required for the excretion of DEQ. The biotransformation of dietary EQ is proven by simultaneous induction of both phase I and II detoxification system in the liver of Atlantic salmon. Therefore, the apparent low concentration of putative DEQ may account for the induced phase I and II detoxifying enzymes at least during depuration. This speculated hypothesis is currently a subject for systematic investigation in our laboratory using in vitro and genomic approaches.     

Synthesis and studies on antioxidants: ethoxyquin (EQ) and its derivatives

In our study ethoxyquin (EQ) and its two complexes with flavonoids were obtained from ethoxyquin (1,2-dihydro-6-ethoxy-2,2,4-trimethylquinoline, EQ) and quercetin (EQ-Q, 1:1) or rutin (EQ-R, 1:1). Cytotoxicity of the tested compounds was studied using the trypan blue exclusion method and the properties of the studied compounds were also analyzed with the TUNEL method evaluating their ability to induce apoptosis. It was shown that EQ induced apoptosis in cultured human lymphocytes, especially at 0.25 and 0.5 mM concentrations. The same effects were also observed after the incubation of lymphocytes with EQ-Q and EQ-R, but the numbers of apoptotic cells observed were lower than for EQ.     

Studies on the metabolism of the antioxidant ethoxyquin, 6-ethoxy-2,2,4-trimethyl-1,2-dihydroquinoline in the rat

1. The metabolism of ethoxyquin (6-ethoxy-2,2,4-trimethyl-1,2-dihydroquinoline) in rat has been investigated. Urinary metabolites were identified by combined g.l.c.-mass spectrometry. 2. The major metabolic reaction was de-ethylation which gave rise to 6-hydroxy-2,2,4-trimethyl-1,2-dihydroquinoline and an oxidation product, 2,2,4-trimethyl-6-quinolone. Other reactions were hydroxylation to four different hydroxylated metabolites and one dihydroxylated metabolite. A total of 95% of the dose (100 mg/kg) was accounted for.     

Ovine urinary metabolites of ethoxyquin.

Metabolites of ethoxyquin (EQ, 1,2-dihydro-6-ethoxy-2,2,4-trimethylquinoline) in the urine of sheep and rats were separated and identified by gas chromatography-mass spectrometry (GC-MS). Sheep were given diets containing EQ or EQ.HCl (0.5% of total diet) and urine samples were collected for the first 24 h and for another 24-h period after 12 d of feeding. Rats were given EQ/corn oil (0.08 g EQ/d/rat) orally for 7 d and urine samples were collected at ambient temperature for a 24-h period following 6 d of dosing. The urine samples were extracted with ethyl acetate at pH 5, and the concentrated extracts were analyzed by GC-MS. Ethoxyquin was identified in all sheep urine samples collected during the first 24 h of feeding, and EQ and hydroxylated EQ were identified in all urine samples collected after 12 d of feeding. In contrast, EQ, hydroxylated EQ, and dihydroxylated EQ were identified in urine collected from rats fed EQ for 7 d.     

Preparation and dietary effects of ethoxyquin hydrochloride

Ethoxyquin (EQ, 1,2-dihydro-6-ethoxy-2,2,4-trimethylquinoline) was purified and converted to a crystalline, stable ethoxyquin hydrochloride (EQ-HCl). The readily available (technical grade) oily EQ reacted with concentrated hydrochloric acid (HCl) and precipitated as a crystalline salt (EQ-HCl) in acetone, leaving most of the impurities in solution. The regenerated free base (EQ) from the EQ-HCl was further purified by silicagel column chromatography to remove several minor contaminants, and the pure unstable EQ was immediately converted into a pure stable salt (EQ-HCl). The dietary administration of EQ-HCl, 0.25 or 0.5% in the feed, induced hepatic and intestinal thiols in mice and provided protection against toxic doses of pyrrolizidine alkaloids. The LD50 values of the 0.125 and 0.25% EQ-HCl-pretreated mice were 94.0 and 98.5 mg/kg, respectively, compared to that of controls, 71.3 mg/kg. The EQ-HCl-supplemented feed appeared to be more palatable, but other effects, such as the hepatic hypertrophy, the tissue thiol induction, and the protective effects, were comparable to those of unpurified EQ.     

DNA damage induced by ethoxyquin in human peripheral lymphocytes

Ethoxyquin (1,2-dihydro-6-ethoxy-2,2,4-trimethylquinoline, EQ) is widely used in various food products and in animal feeds because of its powerful antioxidant activity. This compound was recently found to cause not only many unfavourable side-effects in animals fed with feeds containing it, but also adverse effects in people exposed to it at work. In the present study, DNA damage induced by EQ in human lymphocytes has been assessed. The alkaline single cell gel electrophoresis assay (comet assay) was used to measure DNA damage. The cells were treated for 1 h with EQ doses ranging from 1 to 250 microM in the absence or in the presence of an exogenous metabolic activation system (S9mix). The obtained results showed that EQ-induced DNA damage in human lymphocytes in a dose-dependent manner; the observed DNA fragmentation induced by EQ in the presence of metabolic activation system was always significantly lower, as compared to cells treated with the same doses of EQ alone.     

Studies of the biliary excretion and metabolites of the antioxidant ethoxyquin, 6-ethoxy-2,2,4-trimethyl-1,2-dihydroquinoline in the rat

1. Biliary excretion and metabolites of ethoxyquin, and gastro-intestinal absorption of ethoxyquin were studied in rat. 2. An average of 28 and 36% of the dose of 14C following intragastric administration of [14C]ethoxyquin was recovered in the bile of bile-duct cannulated rats in 12 and 24 h, respectively. 3. By g.l.c.-mass spectrometry, 75 to 85% of the 14C excreted in the 12 h bile was identified as unchanged ethoxyquin, and the following metabolites were isolated and identified: 8-hydroxy-ethoxyquin, hydroxylated 8-hydroxy-ethoxyquin, 6-ethoxy-2,2,4-trimethyl-8-quinolone, hydroxylated 6-ethoxy-2,2,4-trimethyl-8-quinolone, 6-ethoxy-2,4-dimethylquinoline and 2,2,4-trimethyl-6-quinolone. 4. Three groups of rats were used in the biliary excretion experiments, and the effect of standardization of experimental conditions was demonstrated. Infusion of sodium taurocholate following bile-duct cannulation did not affect the biliary excretion kinetics of ethoxyquin. 5. Only about 3% of the radioactivity administered was absorbed from the gastrointestinal tract via the lymphatic pathway in thoracic-duct connulated rats within 24 h. It was concluded that ethoxyquin was absorbed primarily by the portal route.     

Modulation of ethoxyquin genotoxicity by free radical scavengers and DNA damage repair in human lymphocytes

N-tert-butyl-α-phenylnitrone (PBN) and its new derivative N-(Pyridine-4-ylmethylidene)-2-carboxy-tert-butylamine N-oxide (PBNC) were synthesized and used to modulate ethoxyquin (1,2-dihydro-6-ethoxy-2,2,4-trimethylquinoline, EQ) genotoxicity. Ethoxyquin, an antioxidant used mainly as a preservative in animal feeds, was shown to cause DNA breaks in human lymphocytes. The aim of the study was to evaluate the involvement of free radicals in the genotoxicity of EQ and its modulation by cellular repair systems. Human lymphocytes treated with EQ (10–50 μM) and nitrone free radical scavengers (100 μM) were tested with the comet assay. It was shown that both PBN and PBNC reduced the level of EQ-induced DNA damage, but PBN was slightly more effective. The modulation of the level of DNA damage was also observed as a result of DNA repair by cellular repair systems. Moreover, induction of oxidized bases by ethoxyquin was showed; lymphocytes exposed to ethoxyquin and treated with endonuclease III (Endo III) and formamidopyrimidine-DNA glycosylase (FpG), enzymes recognizing oxidized bases, displayed greater extent of DNA damage than those not treated with the enzymes.     

Reversibility of hepatic changes caused by ethoxyquin

Ethoxyquin (6-ethoxy-1,2-dihydro-2,2,4-trimethylquinoline) was administered to rats at a dose level of 0.5 per cent in the diet for 14 days. It caused a marked increase in liver weight and induction of microsomal drug metabolizing enzymes. In contrast glucose-6-phosphatase activity was depressed. During a 30-day recovery period after removal of ethoxyquin the following parameters were monitored at intervals of 0, 3, 7, 14 and 30 days: liver weight, microsomal protein, cytochrome P-450, cytochrome b₅, biphenyl-4-hydroxylase, ethylmorphine-N-demethylase, glucose-6-phosphatase and DNA. Recovery appeared to be biphasic, specific enzyme activity and DNA concentration returning to normal in 3–7 days but, as a result of the slower return to normal liver size, total hepatic enzyme activity did not return to control levels until the 30th day.     

Studies on the Biliary Excretion and Metabolites of the Antioxidant Ethoxyquin, 6-Ethoxy-2,2,4-Trimethyl-1,2-Dihydroquinoline in the Rat

1. Biliary excretion and metabolites of ethoxyquin, and gastro-intestinal absorption of ethoxyquin were studied in rat.

2. An average of 28 and 36% of the dose of¹⁴C following intragastric administration of [¹⁴C]ethoxyquin was recovered in the bile of bile-duct cannulated rats in 12 and 24?h, respectively.

3. By g.l.c.-mass spectrometry, 75 to 85% of the ¹⁴C excreted in the 12?h bile was identified as unchanged ethoxyquin, and the following metabolites were isolated and identified: 8-hydroxy-ethoxyquin, hydroxylated 8-hydroxy-ethoxyquin, 6-ethoxy-2,2,4-trimethyl-8-quinolone, hydroxylated 6-ethoxy-2,2,4-trimethyl-8-quinolone, 6-ethoxy-2,4-dimethylquinoline and 2,2,4-trimethyl-6-quinolone.

4. Three groups of rats were used in the biliary excretion experiments, and the effect of standardization of experimental conditions was demonstrated. Infusion of sodium tauro-cholate following bile-duct cannulation did not affect the biliary excretion kinetics of ethoxyquin.

5. Only about 3% of the radioactivity administered was absorbed from the gastrointestinal tract via the lymphatic pathway in thoracic-duct cannulated rats within 24?h. It was concluded that ethoxyquin was absorbed primarily by the portal route.     

Synthesis and antiproliferative activity in vitro of novel 1,5-benzodiazepines. Part II

The reaction of 2,2,4-trimethyl-1H-2,3-dihydro-1,5-benzodiazepine (1) with cinnamoyl chloride leading to the formation of 1-cinnamoyl derivative 2 is described. Two novel benzodiazepines, 2,2,4-trimethyl-1H-2,3,4,5-tetrahydro-1,5-benzodiazepine (3) and 1-cinnamoyl-2,2,4-trimethyl-1H-2,3,4,5-tetrahydro-1,5-benzodiazepine (4), were synthesized by the reduction of 1 and 2 using NaBH4 in i-PrOH and two other derivatives 5 and 6 were obtained by reaction of 4 with equimolar and dimolar quantity of cinnamoyl chloride, respectively. The structures of 1-6 were confirmed by analytical and spectral data (IR, 1H NMR, and MS). 7-Carboxy-2,2,4-trimethyl-1H-2,3-dihydro-1,5-benzodiazepine (7) was synthesized and its crystals were subjected to X-ray analysis. Benzodiazepines 1-6 were evaluated for antiproliferative activity in vitro. Among the compounds tested, 4-6 exhibited cytotoxic activity against human cancer cell lines, namely SW707 (colon cancer), MCF-7 (breast cancer), A549 (lung cancer), and HCV29T (bladder cancer).     

Discovery of structurally diverse nonsteroidal SPRMs based on a screening hit, 1,2-dihydro-2,2,4-trimethyl-6-phenylquinolinone

Synthetic steroidal progestins and antiprogestins have been widely used for decades to treat many gynecological conditions. The concept of selective progesterone receptor modulators (SPRMs) has been developed in recent years to design new therapeutic agents that have desirable PR modulating activity with significantly reduced side-effects or increased safety margin. This review describes medicinal chemistry progress of multiple nonsteroidal SPRM series based on a screening hit, 1,2-dihydro-2,2,4-trimethyl-6-phenylquinolinone.     

Accumulation and elimination of methylmercury in Atlantic cod (Gadus morhua L.) following dietary exposure

Methylmercury is known to bioaccumulate and biomagnify up the marine food chain. Fish from high levels of the marine food chain may contain relatively high concentrations of mercury, and most (>70%) of the mercury found in muscle is methylmercury. In aquaculture, marine protein (mainly fishmeal) is the dominant source of methylmercury, and this raises some concern with regards to fish welfare and consumer safety. A dietary exposure study, including a depuration period, was carried out in order to study the accumulation and elimination of methylmercury in Atlantic cod (Gadus morhua L.), and to estimate the transfer of methylmercury from feed to fish. Fish were sampled throughout a three month exposure period and a three month depuration period. Muscle samples were fractionated into a protein and a lipid fraction by lipid extraction using methanol and chloroform. Mercury and methylmercury were determined by inductively coupled plasma mass spectrometry (ICPMS) and gas chromatography-inductively coupled plasma mass spectrometry (GC-ICPMS), respectively. A continuous accumulation of methylmercury, after a lag period of 10 days, was observed in muscle tissue during the three months exposure to methylmercury (0.95+/-0.03 microg Hg/g feed, n=6). After three months, the final concentration in muscle was 0.38+/-0.04 microg Hg/g w w (n=6), where methylmercury constituted 90-95% of the mercury present. The elimination of methylmercury from muscle was slow and incomplete (within the three months of depuration) with an estimated elimination half-life (t1/2) of 377 days. The transfer of methylmercury from feed to Atlantic cod, described by the estimated absorption efficiency, was 38%. In muscle more than 99% of the mercury was found in the protein fraction. These results suggest that Atlantic cod readily takes up dietary methylmercury, which is efficiently accumulated into muscle, where it is incorporated into larger peptides or proteins. Comparable results were found for Atlantic salmon (Salmo salar L.). After three months of exposure to dietary methylmercury the final concentration in muscle was 0.33+/-0.01 microg Hg/g w w (n=3), where nearly all (>99%) mercury was found in the protein fraction. This further supports that methylmercury is accumulated in fish muscle, where it is incorporated into larger peptides or proteins.     

Synthesis and characterization of nonsteroidal glucocorticoid receptor modulators for multiple myeloma

Structure-activity relationship studies centered around 3'-substituted (Z)-5-(2'-(thienylmethylidene))1,2-dihydro-9-hydroxy-10-methoxy-2,2,4-trimethyl-5H-chromeno[3,4-f]quinolines are described. A series of highly potent and efficacious selective glucocorticoid receptor modulators were identified with in vitro activity comparable to dexamethasone. In vivo evaluation of these compounds utilizing a 28 day mouse tumor xenograft model demonstrated efficacy equal to dexamethasone in the reduction of tumor volume.     

Carcinogenicity of dermally administered 1,2-dihydro-2,2,4-trimethylquinoline monomer in F344 rats and B6C3F1 mice

1,2-Dihydro-2,2,4-trimethylquinoline (TMQ) was evaluated in a 2-year study in which groups of 60 male or female F344 rats received 0, 36 or 60 mg kg(-1) (0, 0.022, or 0.037 mg cm(-2)) and groups of 60 male or female B6C3F1 mice received 0, 3.6 or 10 mg kg(-1) (0, 0.00136, 0.00435 mg cm(-2)) in acetone by topical administration. Survival of all treated groups was comparable to survival of controls. Mean body weights of female rats were lower than those of controls throughout the study but mean body weights of male rats and male and female mice were comparable to the mean body weights of controls. No neoplasms of the skin were observed in any group of rats or mice. Acanthosis at the site of application was increased in male and female rats that received 60 or 100 mg kg(-1) and hyperkeratosis was increased in female rats that received 60 mg kg(-1). The incidences of renal tubule adenoma and renal tubule adenoma or carcinoma were increased significantly in the 60 and 100 mg kg(-1) groups of male rats. There were no neoplastic or non-neoplastic lesions in mice associated with exposure to 1,2-dihydro-2,2,4-trimethylquinoline. In a 1-year initiation-promotion study, groups of 30 female SENCAR mice received an initiating dose of 50 mg kg(-1) 1,2-dihydro-2,2,4-trimethylquinoline followed by promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA), or an initiating dose of 7,12-dimethylbenzanthracene (DMBA) followed by promotion with 5, 10 or 25 mg kg(-1) 1,2-dihydro-2,2,4-trimethylquinoline. Other groups served as initiator control, promoter control, vehicle control and positive control (DMBA initiation, TPA promotion). In this system, 1,2-dihydro-2,2,4-trimethylquinoline-initiated skin was not promoted by TPA, and DMBA-initiated skin was not promoted by 1,2-dihydro-2,2,4-trimethylquinoline.     

Accumulation and elimination kinetics of dietary endosulfan in Atlantic salmon (Salmo salar)

The carry-over of dietary endosulfan to the fillet of farmed Atlantic salmon was studied. The uptake and elimination rate constants of the alpha and beta isoform of endosulfan were determined in seawater adapted Atlantic salmon (initial weigh 173+/-25 g) fed on endosulfan enriched diets (724 and 315 microg kg(-1) for alpha- and beta-endosulfan, respectively) for 92 days, followed by a 56 days depuration period with feeding on control diets (<0.3 microg kg(-1) endosulfan). The accumulation of the toxic metabolite endosulfan sulphate, which was not detected (<0.5 microg kg(-1)) in the experimental feeds, was also determined. Dietary beta-endosulfan was more persistent than alpha-endosulfan as demonstrated by a higher uptake (41+/-8% vs. 21+/-2%) and lower elimination (26+/-2 x 10(-3) day(-1) vs. 40+/-1 x 10(-3) day(-1)) rate constants, and a higher biomagnification factor (0.10+/-0.026 vs. 0.05+/-0.003, p<0.05). Based on the decrease in diastereometric factor over time, biotransformation was estimated to account for at least 50% of the endosulfan elimination. The formation of the metabolite endosulfan sulphate comprised a maximum 1.2% of the total accumulation of endosulfan. Using a simple one-compartmental model and the experimentally-determined rate constants, it was predicted that only dietary concentration higher than 7.5 mg kg(-1) would cause the estimated maximum residue level (MRL) in fillet of 0.47 mg kg(-1) to be exceeded. Model estimations also predict that current EU maximum permitted levels in fish feeds (0.005 mg kg(-1)) would give fillet concentrations that are under the detection limit (0.3 microg kg(-1)), which is in agreement with the general absence of endosulfan in monitored farmed Atlantic salmon.     

Absorption, distribution, metabolism, and excretion of 1,2-dihydro-2,2,4-trimethylquinoline in the male F344 rat

1,2-Dihydro-2,2,4-trimethylquinoline (TMQ), an antioxidant used in the rubber industry, was readily absorbed from the gastrointestinal tract of the male Fischer 344/N rat and rapidly distributed throughout the body tissues. Absorption, distribution, metabolism, and excretion were not significantly affected by dose in the range 11.5-1150 mumol/kg. Following iv administration, the greatest amounts of TMQ-derived radioactivity were present in the high volume tissues including muscle, adipose, skin, liver, and blood. TMQ had no particular affinity for any tissue. TMQ-derived radioactivity was excreted primarily in urine (60-70%) and feces (20-30%) within 3 days after administration. Greater than 99% of the TMQ dose excreted in urine and feces was in the form of metabolites. Urine contained two major and ten minor metabolites while feces contained two major and four minor metabolites. The two major TMQ metabolites in urine were identified by NMR and mass spectroscopy as the O-sulfate conjugate of 1,2-dihydro-6-hydroxy-2,2,4-trimethylquinoline and the monosulfate conjugate of 1,2-dihydro-1,6-dihydroxy-2,2,4-trimethylquinoline. In vitro studies with liver subcellular fractions suggest that most of the metabolites present in urine, feces, and bile are the products of mixed function oxidase activity and conjugates of these metabolites. Multiple exposure of rats to high TMQ doses (1150 mumol/kg) resulted in some bioaccumulation of TMQ-derived radioactivity in all tissues examined, but these residues did not persist when dosing was discontinued.     

Risk and benefits from consuming salmon and trout: a Canadian perspective.

Recent reports on the presence of persistent organic chemicals in wild and farmed salmon have left consumers and health professionals confused regarding the safety of regular fish consumption. The objectives of this study were (1) to compare concentrations of key contaminants and the essential nutrients omega-3 fatty acids between farmed and wild salmon and trout, and (2) to balance risks and benefits from regularly consuming these species. Concentrations of mercury, polychlorinated biphenyls, dioxins and furans as well as omega-3 fatty acids were determined in fillets from farmed salmon and trout bought in various markets located in Quebec, Canada, as well as in fillets from wild salmonids obtained from fishermen and various Canadian agencies. While differences were observed between market (farmed) and wild fish with regard to the concentrations of mercury and polychlorinated biphenyls, overall the concentrations of contaminants were low, such that the regular consumption of these fish would not cause tolerable daily intakes to be exceeded. Our results indicate that salmon and trout sold in Quebec markets, which as in markets located elsewhere in North America originate for the most part from Chilean farms, can be consumed regularly to achieve optimal nutritional benefits from omega-3 fatty acids, without incurring significant contaminant related health risks.     

Pharmacokinetics of thiamine in female Baltic salmon (Salmo salar L.) broodfish

A thiamine deficiency disease termed M74 syndrome affects the yolk-sac fry of wild and feral Baltic salmon. However, very little is known about the pharmacokinetics of thiamine in salmon. This study examined the pharmacokinetics of thiamine hydrochloride injected intraperitoneally into feral and farmed Baltic salmon females preparing for spawning. The total thiamine concentrations in the eggs and white muscle of feral females were only half of those in the farmed fish after injection. The relative inefficiency of the incorporation of thiamine into the eggs in feral Baltic salmon may be a predisposition factor for M74 syndrome. The relative bioavailability of intraperitoneally-injected thiamine hydrochloride was shown to be ca. 94% of that administered intra-aortically. A far lower intraperitoneal dose (ca. 20mgkg(-1) fish) than currently used was shown to elevate the total thiamine concentration in the eggs above the critical threshold of M74 syndrome.