Content of N-nitrosamines in smoked fish and canned food

The composition and contents of major N-nitrosoamines (NA) in the edible part of herrings and rock trouts exposed to hot and cold smoking and in the Smoked fish in oil type cans were studied. Among NA, only N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) were detected in all samples. In the cold-smoked fish, the levels of NDMA and NDEA were higher than in the hot smoked fish and cans. Of all the samples, only those of cold smoked herrings and rock trouts had standardized NDMA concentration that was greater than the standard limitation and equal to 3.48 and 3.74 mukg/kg.     

Concentration of dimethylnitrosamine in the air of smoke-filled rooms

In order to evaluate the contribution of volatile nitrosamines from tobacco smoke to indoor air pollution, N-nitroso-dimethylamine (NDMA) and N-nitroso-diethylamine (NDEA) were measured in indoor air under artificial and natural conditions. In controlled experiments under extreme conditions, we found that tobacco smoke-related NDMA levels above 0.07 ng/liter were associated with a highly irritating atmosphere which was scarcely tolerable to those present. In smoke-filled rooms under natural conditions NDMA levels ranged from 0.02 to 0.05 ng/ liter, except a minimum value of <0.01 ng/liter in a restaurant and a maximum of 0.07 ng/ liter in a dancing bar. These NDMA levels are thus below comparable values reported by others. The NDMA/NDEA ratios found in air samples taken from some rooms under conditions of everyday life are quite different from those found in sidestream smoke of cigarettes. Irritation was not reported under natural conditions. From the results it is concluded that NDMA levels, measured under real life conditions, are usually not caused by tobacco smoke alone. Evidence for other sources of volatile nitrosamines is discussed.     

胃癌高发区酸煎饼汁真菌菌相,致突变性及亚硝胺含量

Sour corn-soybean cake is the main food of the inhabitants in high incidence area of stomach cancer in Linqu county Shandong province. In the extract of the sour corn-soybean cakes, twelve mycotoxin-producing fungi and 3 N-nitrosamines (NDMA, NDEA, NMEA) were detected and the finding rates of the fungi and the N-nitrosamines were 93.3% and 92.3%, respectively; the concentration of NDMA was 0.4-3.8 ng/ml, NDEA 0.2-8.1 ng/ml, and NMEA 0.3-1.4 ng/ml. The positivity rate of the Ames test (most positive materials were direct mutagens) was 44.12%. The experimental results showed that the extract of the sour corn-soybean cakes containing carcinogenic and mutagenic subjects could have some causal relationship with the incidence of stomach cancer.     

我国南方食管癌高发区膳食亚硝胺水平及其相关因素研究

广东省南澳县是我国南方食管癌高发区。环境中可疑病因——亚硝胺及其前体物正日益受到人们的关注。为此，我们从当地居民所吃膳食中采集５５份样品，用ＧＣ－ＴＥＡ测定挥发性亚硝胺及其前体物。样品中检出二甲基亚硝胺（ＮＤ－ＭＡ）、二乙基亚硝胺（ＮＤＥＡ）、亚硝基吡咯烷（ＮＰＹＲ）、亚硝基哌啶（ＮＰＩＰ）及甲基苄基亚硝胺（ＮＭＢｚＡ）。它们的平均水平（中位数）为３１２．０μｇ／ｋｇ，人均日摄入总量为２８６．５μｇ。通过逐步回归及曲线拟合法研究亚硝胺、前体物及主要食物类型间的相关关系。结果表明：该地区膳食中挥发性亚硝胺含量较高。     

藠头和苦瓜汁抑制亚硝胺合成的体外试验

本文报告了在模拟人胃液条件下，头（ＡｌｌｉｕｍｃｈｉｎｅｎｓｉｓＧ．Ｄｏｎ．）和苦瓜（ＭｏｍｏｒｄｉｅａｃｈａｒａｎｔｉａＬｉｎｎ．）对Ｎ－二甲基亚硝胺（ＮＤＭＡ）和Ｎ－二乙基亚硝胺（ＮＤＥＡ）体外合成的阻断作用。结果表明：鲜头汁能明显地阻断ＮＤＭＡ和ＮＤＥＡ的化学合成，而鲜苦瓜汁对ＮＤＭＡ和ＮＤＥＡ的化学合成仅有一定的阻断作用；头经煮沸２０ｍｉｎ和盐腌两周后，其阻断作用大大降低，而同样处理对苦瓜的影响却较小；鲜头升和鲜苦瓜汁的剂量与ＮＤＭＡ和ＮＤＥＡ的合成量呈显著的负相关关系；头阻断亚硝胺合成的主要有效成分并不是抗坏血酸，而苦瓜中抗坏血酸的阻断作用却较大；头和苦瓜阻断亚硝胺合成的机理在于头和苦瓜中的有效成分能消除反应液中的亚硝酸盐     

Presence of Nitrosamine Impurities in Medicinal Products

In 2018, some sartan medicinal products were reported to be contaminated with nitrosamine compounds, which are potent mutagenic carcinogens. Two nitrosamines received particular attention: N -nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA). These have since been confirmed in different types of medicinal products, including ranitidine and metformin. Consequently, the European Medicines Agency (EMA) started an investigation into the cause of contamination and an assessment of the risk to patients taking contaminated medicinal products. The main source of contamination were changes in production, which involves combinations of amines and nitrogen compounds and the use of specific catalysts and reagents. Withdrawals of medicinal products that took place in Croatia did not lead to a shortage of sartan- or metformin-containing medicines. Moreover, ranitidine had been preventively withdrawn all over the EU, including Croatia, creating shortages at the time, but was subsequently replaced with therapeutic alternatives.Key Words: carcinogenicity, metformin, NDEA, NDMA, ranitidine, sartans     

Estimation of the total daily oral intake of NDMA attributable to drinking water

Disinfection with chlorine and chloramine leads to the formation of many disinfection by-products including N-Nitrosodimethylamine (NDMA). Because NDMA is a probable human carcinogen, public health officials are concerned with its occurrence in drinking water. The goal of this study was to estimate NDMA concentrations from exogenous (i.e., drinking water and food) and endogenous (i.e., formed in the human body) sources, calculate average daily doses for ingestion route exposures and estimate the proportional oral intake (POI) of NDMA attributable to the consumption of drinking water relative to other ingestion sources of NDMA. The POI is predicted to be 0.02% relative to exogenous and endogenous NDMA sources combined. When only exogenous sources are considered, the POI was predicted to be 2.7%. The exclusion of endogenously formed NDMA causes the POI to increase dramatically, reflecting its importance as a potentially major source of exposure and uncertainty in the model. Although concentrations of NDMA in foods are small and human exposure to NDMA from foods is quite low, the contribution from food is predicted to be high relative to that of drinking water. The mean concentration of NDMA in drinking water would need to increase from 2.1 x 10(-3) microg/L to 0.10 microg/L, a 47-fold increase, for the POI to reach 1%, relative to all sources of NDMA considered in our model, suggesting that drinking water consumption is most likely a minor source of NDMA exposure.     

Sanitary standardization of 1-carbamoyl-3(5)-methylpyrazole, N-hydroxymethyl-3(5)-methylpyrazole and 4-amino-1,2,4-triazole in the water of reservoirs]

Since there is a problem in the sanitary protection of water reservoirs, nitrification inhibitors (NI), such as CMP, HMMP, ATG, were tested for their effects on the organoleptic properties and sanitary regimen of model water basins. The threshold concentrations of the inhibitors were found to be 0.49, 230, and 229 mg/l, respectively. The agents were classified as highly stable. They failed to affect on self-clearance. In chronic intoxication, the inactive doses were 0.128 mg/kg for CMP, 0.165 mg/kg for HMMP, and 1.36 mg/kg for ATG (1/1000 of LD50). The maximum allowable water concentrations were 0.01, 0.01, and 0.1 mg/l, respectively (in the context of complex sanitary standardization). The limiting hazard index was sanitarily toxicological (Hazard Class 3).     

Detection and toxicity assessment of nitrosamines migration from latex gloves in the Chinese market

Nitrosamines are potent carcinogens and have been found in latex products. In 2007, twenty-seven natural latex gloves including sterile gloves, examination gloves and household use gloves were sampled from the Chinese market. This study monitored the migration of nitrosamines and nitrosatable substance from these gloves, and evaluated their mutagenicity using a Salmonella typhimurium mutation assay (Ames assay) with the strains TA98, TA97, TA100 and TA102 and by a micronucleus test (MN test) using ICR mice. In addition, the cytotoxicity of these compounds was determined by a MTT assay. N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA) and N-nitrosodibutylamine (NDBA) were all found in samples treated with artificial sweat for 4 h at 37 °C, and total nitrosamines varied from 18.89 to 244.51 μg/Kg. The nitrosamine mixture of NDMA, NDEA and NDBA was used in both the Ames assay and the MN test. The proportion of NDMA, NDEA and NDBA (1:10:20) was selected according to the proportion of nitrosamines migration from sample E05. In the Ames assay, the lowest dose (1.98×10⁻³ μg per plate) produced a positive result in the TA98 strain, corresponding to nitrosamines migration from sample E05 of 0.016 g (the total nitrosamines migration from glove E05 was 122.55 μg/kg). The TA100 strain responded positively at a dose of 4.96×10⁻² μg per plate, corresponding to nitrosamines migration from glove E05 of 0.040 g. The MN test showed nitrosamine migration of 3.04 mg from 2066 pairs of sample E05 and could induce micronuclei in one mouse weighing 28 g (average weight of one E05 glove was 6 g). Extracts from gloves were found to be cytotoxic and there was a significant correlation between cytotoxicity (IC₅₀) and the release level of nitrosamines. In conclusion, in view of the high content of nitrosamines in latex gloves and the potential toxicity of nitrosamines migration from these gloves, it is suggested that both an effective and feasible detection method and prescribed limits should be imposed.     

Estimation of the total daily oral intake of NDMA attributable to drinking water

Disinfection with chlorine and chloramine leads to the formation of many disinfection by-products including N-Nitrosodimethylamine (NDMA). Because NDMA is a probable human carcinogen, public health officials are concerned with its occurrence in drinking water. The goal of this study was to estimate NDMA concentrations from exogenous (i.e., drinking water and food) and endogenous (i.e., formed in the human body) sources, calculate average daily doses for ingestion route exposures and estimate the proportional oral intake (POI) of NDMA attributable to the consumption of drinking water relative to other ingestion sources of NDMA. The POI is predicted to be 0.02% relative to exogenous and endogenous NDMA sources combined. When only exogenous sources are considered, the POI was predicted to be 2.7%. The exclusion of endogenously formed NDMA causes the POI to increase dramatically, reflecting its importance as a potentially major source of exposure and uncertainty in the model. Although concentrations of NDMA in foods are small and human exposure to NDMA from foods is quite low, the contribution from food is predicted to be high relative to that of drinking water. The mean concentration of NDMA in drinking water would need to increase from 2.1 × 10^-3 mg/L to 0.10 mg/L, a 47-fold increase, for the POI to reach 1%, relative to all sources of NDMA considered in our model, suggesting that drinking water consumption is most likely a minor source of NDMA exposure.     

Total antioxidant status in the blood serum of rats exposed to N-nitroso compounds and nitric oxide synthase inhibitors

In this study, the total antioxidant status (TAS) was assayed in the blood serum of rats pretreated per os with either N-nitrosodiethylamine (NDEA) (0.1 mg/kg b.w./day) or N-methyl-N-nitrosourea (NMU) (0.1 mg/kg b.w./day) for 30 days. The animals were also dosed per os with spermidine (SPR) (10 mg/kg b.w./day) for a first 21 day period, and Nomega)-nitro-L-arginine methyl ester (L-NAME) (10 mg/kg b.w./day) given to animals for 3 days (days 22-24), respectively. Nitric oxide synthase (NOS) inhibitor, L-NAME was found to mitigate TAS levels in the blood serum of rats pretreated with NDEA and NMU. No such changes were found in animals dosed with L-NAME only nor even with L-NAME and spermidine, respectively. Since spermidine, also known as an inhibitor of iNOS synthesis, elevated TAS levels in rats dosed with L-NAME and NDEA/NMU, the polyamine was suggested to modify the NOS/NO origin to serve the physiological level of the total anti-oxidant status in rat blood serum.     

Carcinogenic hazard of nitrosodimethylamine in humans

Literary data on the evaluation of carcinogenic hazard of nitroso compounds and in particular nitrosodimethylamine (NDMA) were analyzed. Their hazardous impact on humans was confirmed. The study results enabled one to set the total safety dose of NDMA at 0.1 mg per animal, to determine NDMA safety levels in environment, i.e., atmospheric air and water reservoirs, at. 0.0001 mg/m3 and 0.0001 mg/l, respectively, and to establish the total human safety level of NDMA at less than 0.002 mg per day.     

Leaching risk of N-nitrosodimethylamine (NDMA) in soil receiving reclaimed wastewater

N-nitrosodimethylamine (NDMA) is a potential carcinogen frequently found in treated wastewater as a byproduct of chlorination. The potential for NDMA to contaminate the groundwater is a significant concern. A solute fate and transport model, Hydrus-1D, was used to evaluate the leaching potential of NDMA under different irrigation practices and soil properties. The results indicate that the risk of NDMA to reach the ground water is slim, when the reclaimed wastewater is applied under the customary conditions for landscape irrigation. The NDMA disappears in the reclaimed wastewater receiving soils rapidly through the microbial degradation and the volatilization processes. The factors that enhance the leaching risk are the soil hydraulic conductivity, the NDMA adsorption constants, and the irrigation intensity. When the hydraulic conductivity of soil is high, the NDMA adsorption constant of soil is low and/or the irrigation intensity is high, the NDMA leaching risk may dramatically increase. To reduce the NDMA leaching risk, it is imperative that the fields be irrigated at the proper volume and frequency and attention be paid to fields with soils having high-hydraulic conductivities and/or low-NDMA adsorption constants.     

Occurrence of nitroso compounds in fungi-contaminated foods: a review

Dimethylnitrosamine (NDMA), diethylnitrosamine (NDEA), methylbenzylnitrosamine, and a new N-nitroso compound, N-3-methylbutyl-N-1-methylacetonylnitrosamine (NMAMBA), were found in cornbread that was inoculated with Fusarium moniliforme and underwent an incubation and the addition of a small amount of NaNO2. The carcinogenicity of NMAMBA was shown by the induction of forestomach carcinomas and liver tumors in mice and rats. Another new nitrosamine, N-2-methylpropyl-N-methylacetonyl nitrosamine, was isolated in millet and wheat flour after similar treatment. Some species of fungi not only can reduce nitrates to nitrites but also can increase the amount of secondary amines in the moldy foods and provide favorable conditions for the synthesis of nitrosamines. Some fungi may utilize primary amines to synthesize nitrosamines in appropriate culture mediums. Furthermore, the cornmeal may naturally contain trace amounts of nitrosamines, as detected by a gas chromatography/thermoenergy analyzer. Prolonged feeding of F. moniliforme-inoculated cornbread alone also induced the development of forestomach carcinoma in rats. This indicates the occurrence of potential carcinogens, perhaps certain Fusarium mycotoxins, in the moldy cornbread in addition to the carcinogenic nitrosamines. Another nitroso compound, Roussin red methylester (di-mu-methanethiolatotetranitrosodiiron) was found in pickled vegetables that are eaten daily in the Linxian (China) area. Roussin Red may provide NO-2 ions, which would react readily with secondary amines to form nitrosamines. Possibly this compound is a natural tumor promoter and is able to induce epithelial hyperplasia of the upper digestive tract and forestomach papilloma in treated mice. Also, trace amounts of NDMA, NDEA, and some other nitrosamines were found in the extract of pickled vegetables.     

Lycopene Enriched Tomato Extract Inhibits Hypoxia,Angiogenesis, and Metastatic Markers in early Stage N-Nitrosodiethylamine Induced Hepatocellular Carcinoma

Targeting altered pathways during initial stage of hepatocellular carcinoma (HCC) development is viewed as an effective and promising strategy to control this disease. Present study investigated the potential effect of lycopene-enriched tomato extract (LycT) on hypoxia-induced factor (HIF)-1α, HOX, VEGF, CD31, matrix metalloproteinase (MMP)-2, MMP-9, and alpha fetoprotein (AFP)expression during initial stages of N-nitrosodiethylamine (NDEA) induced HCC. Female Balb/c mice (8–10 wk) were assigned to 4 groups: control, NDEA (200 mg NDEA i.p./kg body weight, cumulative), LycT (5 mg lycopene orally/kg body weight; 3 times a week), and LycT + NDEA. LycT treatment began 2 wk before NDEA administration and continued until the end of the 10 wk study. The onset of HCC by NDEA was associated with significant alteration in serum biochemical markers [alanine transaminases (ALT), aspartate transaminases (AST), and alkaline phosphatases (ALP), lactate dehydrogenase (LDH), urea, A/G ratio, and bilirubin] and in liver histopathology. LycT treatment significantly reduced the levels of these markers. LycT treatment to NDEA mice also led to significant reduction in protein levels of AFP, HIF-1α, VEGF, CD31, MMP-2, and MMP-9 in comparison with NDEA group alone. These parameters are important biomarkers of hypoxia, angiogenesis, and metastasis, which reflect the advanced disease stage. The study provides evidence that prophylactic dietary supplementation with LycT may counteract HCC progression and/or protect against disease onset.     

Atmospheric concentrations of polycyclic aromatic hydrocarbons during chimney sweeping

Air sampled from the breathing zone of chimney sweeps during "dirty work" and soot samples were analysed for polycyclic aromatic hydrocarbons (PAH). A total of 20 PAH were quantified by gas chromatography-mass spectrometry in 115 air samples and 18 soot samples. These included benzo(b)fluoranthene, benzo(a)pyrene (BaP), chrysene, dibenz(a,h)anthracene, and indeno (1,2,3-cd)pyrene, all of which are animal carcinogens. The summed atmospheric concentration of these compounds depended on the type of fuel used and averaged 2.27 micrograms/m3 for oil fuel. If a mixture of oil and solid fuel was used the concentration was 5.06 micrograms/m3; pure solid fuel heating yielded 5.08 micrograms/m3. The air concentrations of BaP were 0.36, 0.83, and 0.82 micrograms/m3 respectively. The soot samples recovered after using the three different fuel types were 10.50, 109.10, and 51.25 mg BaP/kg. The maximum total concentrations of the five carcinogenic PAH were 243.70, 691.06, and 213.94 mg/kg respectively. The time weighted, shift mean concentrations of 0.02 to 0.21 micrograms/m3 benzo(a)pyrene obtained on 11 days form the basis for the industrial medical estimation of risk.     

Repletion of folate-depleted rats with an amino acid-based diet supplemented with folic acid

Folate depletion and repletion protocols are not well standardized. Weanling rats were moderately depleted of folate in 28 d with a folate-free purified diet based on 17% amino acids as the nitrogen source. They were then folate repleted for 23 d with the amino acid diet supplemented with either 125, 250, 500, 1000 or 2000 micrograms folic acid/kg. Hematology, growth and tissue folate levels were measured in subsets of the rats when they were 24 (baseline), 52 (depleted) and 75 d old (repleted). The same measurements were made in control rats that had been fed 2 mg folic acid/kg of the amino acid diet for the same period of time. Our findings show that with repletion, growth of previously depleted rats is in direct proportion with the level of supplementation up to 1000 micrograms folic acid/kg diet. Serum folate levels of repleted rats also increased in proportion to supplementation between 500 to 2000 micrograms/kg diet, and liver folate levels increased proportionally with the level of supplement within the range of 125 to 2000 micrograms/kg diet. The 2000 micrograms/kg supplement was sufficient to restore liver folate levels equivalent to that of controls, but body weight and serum folate levels failed to catch up with that of controls in the 23-d repletion period. There was a nonlinear relationship between serum and liver folate levels: serum folate remained constant at about 6 micrograms/l as liver folate increased to about 7 micrograms/g, then serum folate diverged by increasing to 120 micrograms/l with only minor increases in liver folate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Atmospheric concentrations of polycyclic aromatic hydrocarbons during chimney sweeping.

Air sampled from the breathing zone of chimney sweeps during "dirty work" and soot samples were analysed for polycyclic aromatic hydrocarbons (PAH). A total of 20 PAH were quantified by gas chromatography-mass spectrometry in 115 air samples and 18 soot samples. These included benzo(b)fluoranthene, benzo(a)pyrene (BaP), chrysene, dibenz(a,h)anthracene, and indeno (1,2,3-cd)pyrene, all of which are animal carcinogens. The summed atmospheric concentration of these compounds depended on the type of fuel used and averaged 2.27 micrograms/m3 for oil fuel. If a mixture of oil and solid fuel was used the concentration was 5.06 micrograms/m3; pure solid fuel heating yielded 5.08 micrograms/m3. The air concentrations of BaP were 0.36, 0.83, and 0.82 micrograms/m3 respectively. The soot samples recovered after using the three different fuel types were 10.50, 109.10, and 51.25 mg BaP/kg. The maximum total concentrations of the five carcinogenic PAH were 243.70, 691.06, and 213.94 mg/kg respectively. The time weighted, shift mean concentrations of 0.02 to 0.21 micrograms/m3 benzo(a)pyrene obtained on 11 days form the basis for the industrial medical estimation of risk.     

Occurrence of lead-related symptoms below the current occupational safety and health act allowable blood lead levels

To determine the occurrence of symptoms of lead toxicity at levels below the current allowable Occupational Safety and Health Act blood lead level of 50 micrograms/dL, standardized telephone interviews were conducted of individuals reported to a statewide laboratory-based surveillance system. Four hundred and ninety-seven, or 75%, of the eligible participants were interviewed. Gastrointestinal, musculoskeletal, and nervous system symptoms increased with increasing blood lead levels. Nervous, gastrointestinal, and musculoskeletal symptoms all began to be increased in individuals with blood leads between 30-39 micrograms/dL and possibly at levels as low as 25-30 micrograms/dL for nervous system symptoms. The results of this study of increased symptoms are consistent with and provide added weight to previous results showing subclinical changes in the neurologic and renal systems and sperm counts at blood lead levels currently allowed by the Occupational Safety and Health Act.     

Longitudinal manganese and copper balances in young infants and preterm infants fed on breast-milk and adapted cow's milk formulas

1. Mn and Cu intake and retention in twenty full-term infants and six preterm infants were studied on the basis of 72 h balances. The age of the infants was 2-16 weeks and the gestational age of the preterm infants (triplets) 34 and 36 weeks. Three nutrition schemes were pursued: breast-fed, formula-fed with unsupplemented adapted formula and formula-fed with trace element supplementation. 2. The mean Mn concentration of all breast-milk samples (n 2339) was 6.2 micrograms/l. The two formulas had similar Mn concentrations (77 and 99 micrograms/l) but had different Fe, Cu (121 and 619 micrograms/l), Zn and I contents. The mean Cu concentration in mother's milk was 833 micrograms/l. 3. The following mean daily Mn intakes and retentions (micrograms/kg) respectively were measured: breast-fed full-term 1.06 (SD 0.43) and 0.43 (SD 0.65), formula-fed full-term 14.2 (SD 3.1) and 2.8 (SD 4.8), formula-fed preterm 15.0 (SD 2.2) and 0.06 (SD 5.87). The results for Cu were 114.5 (SD 22.3) and 88.0 (SD 46.5) micrograms/kg in breast-fed, 19.8 (SD 4.2) and 4.6 (-11.5-9.6) in the unsupplemented formula-fed and 106.4 (SD 18.9) and 55.5 (SD 20.3) in the supplemented formula full-term infant group. No significant influence of the trace element contents of the formulas on the relative retention of Mn or Cu was found. 4. Young preterm infants, and to some degree young full-term infants, often had negative Mn balances caused by a high faecal excretion. The formulas with a Mn concentration below 100 micrograms/l gave a sufficient supply of Mn. Preterm infants fed on the unsupplemented formula had a marginal Cu supply and their first balances were negative (-3.8 (SD 1.8) micrograms/kg). 5. In accordance with the estimated safe and adequate daily dietary intakes (recommended dietary allowances), formula-fed infants receive much more Mn than breast-fed infants and their absolute retention is higher. 6. Cu from breast-milk had a significantly better biological availability than that from cow's milk formula. If retentions similar to those in breast-fed infants are intended, we conclude, therefore, that cow's milk formula should be fortified with Cu up to a level of at least 600 micrograms/l.