• Mendelian randomization.

      Brennan, Paul; Hung, Rayjean (Nofer Institute of Occupational Medicine, 2008)
    • Oxidative damage.

      Olinski, Ryszard; Loft, Steffen; Nair, Urmila; Nair, Jagadeesan (The Nofer Institute of Occupational Medicine, 2006)
      Free radical attack upon DNA generates, among other changes, modified bases. The amount of 8-oxo-7,8-dihydroguanine, one of the most critical lesions in human lymphocytes, was found to be 1.2/106. Gua by a mass spectrometric approach. Spurious oxidation occurring during sample preparation is the major problem in measurement of oxidised bases in DNA. Exposure to ambient air particles and benzene is associated with higher levels of 8-oxo-7,8-dihydroguanine and other oxidatively modified bases. Studies of the effects of antioxidant supplements and antioxidant-rich food have given contradictory results. New techniques allowing the simultaneous determination of 8-oxo-7,8-dihydro-2’-deoxyguanosine, 8-oxo-7,8-dihydroguanine and 5-methylhydroxy-uracil in urine samples have revealed that the combined amount of these compounds excreted into urine of healthy human subjects corresponds to about 2800 oxidative modifications of guanine per cell per day. Cohort studies are required to assess whether an increased level of biomarkers of oxidative DNA damage is associated with an increased risk of developing cancer. Lipid peroxidation resulting from chronic inflammatory processes can result in production of excess reactive oxygen and reactive nitrogen species and DNA-reactive aldehydes, including 4-hydroxy-2-nonenal, malonaldehyde, acrolein, and crotonaldehyde. Alkylation of DNA bases by these reactive electrophiles is thought to contribute to the mutagenic and carcinogenic effects associated with oxidative stress-induced lipid peroxidation. The specific and sensitive methods developed for the detection of these potentially mutagenic adducts in human tissues and in urine have been applied to the analysis of DNA from a variety of normal and disease-related samples.
    • Phase I enzyme genotypes and their toxicologically relevant phenotypes.

      Godschalk, Roger; van Schooten, Frederik Jan (Nofer Institute of Occupational Medicine, 2008)
    • Phase II enzyme genotypes and their toxicologically relevant phenotypes.

      Hirvonen, Ari (Nofer Institute of Occupational Medicine, 2008)
    • Phosphotriesters: Long lifetime biomarkers.

      Le Pla, Rachel C.; Jones, G. Don D.; University of Leicester, UK (The Nofer Institute of Occupational Medicine, 2006)
      In addition to reacting with DNA bases, many genotoxic agents react with the oxygen of the internucleotide phosphodiester linkages to form phosphotriester adducts. Several studies have shown that phosphotriester lesions have a half-life that exceeds that of any other DNA alkylation product. The relative abundance of phosphotriesters depends upon the alkylating character of the agent. The role of phosphotriester adducts in carcinogenesis is unknown. Mutation resulting from phosphotriester formation has not been fully studied, but such adducts may influence cellular function by altering the binding of proteins to DNA.
    • Selenoproteins and selenium speciation in food.

      Hoac, T.; Lundh, T.; Onning, G.; Akesson, B. (Zhejiang University Press : Springer, 2012)
      Different forms of selenium may have varying bioavailability and may also have different effects on body physiology. For these reasons we have studied the occurrence of different forms of selenium in some foods. The pattern of soluble selenium compounds in different species of fish varied markedly as studied by size-exclusion chromatography coupled to ICP-MS or GFAAS. Most flatfish contained mainly low-molecular-weight selenium compounds while other fish species contained more protein-bound selenium. Studies of muscle from seven meat animal species showed four major selenium peaks as found by size-exclusion chromatography. The second and third peaks probably corresponded to glutathione peroxidase (GPx) and selenoprotein W, respectively, and they contained 85% –100% of the recovered selenium. The distribution among the four peaks of soluble selenium varied considerably among muscles from different species. In other experiments, several factors were found to affect the activity of GPx in tissues such as species differences, tissue specificity and heating. In bovine milk, another selenium-rich food, GPx3 is the only identified selenoprotein so far. Bovine whey was found to contain most of the selenium in β-lactoglobulin, α-lactalbumin and selenomethionine. Supplementation of the cow’s feed by yeast selenium increased the proportion of selenium in the former two fractions. It can be concluded that different animal foods contain a variety of selenium compounds and that the selenium profiles of fish, meat and milk differ markedly and also show species differences. The role of this diversity for the bioavailability of selenium from different foods and the effects of different forms of selenium on the organism need to be explored.
    • Sensitivity and specificity of techniques for the identification of biomarkers.

      Farmer, Peter B.; Phillips, David; Moller, Lennart; Singh, Raj; van Schooten, Frederik-Jan; Godschalk, Roger; Mateuca, Raluca; Kirsch-Volders, Micheline (The Nofer Institute of Occupational Medicine, 2006)
      The approaches described for the determination of DNA adducts mostly reach sensitivity limits in the range of 1 adduct/107–109 nucleotides and are thus applicable for studies of environmental exposure to genotoxins. Availability of DNA may be a limiting feature and the kind of sample required will determine how a method is used in human biomonitoring studies. Protein adducts are generally stable and are therefore very suitable for use as biomarkers of exposure. The sensitivity of the mass spectral approaches for these assays has been shown to be sufficient for detection of adducts at low pmol/g protein levels. However, there is a lack of a screening method for characterisation of exposures to complex mixtures and no really high throughput analytical methods,preferable for large-scale human molecular epidemiological studies, exist. Structural chromosomal aberrations in peripheral blood lymphocytes have been widely used in occupational and environmental settings as a biomarker of early effects of geno-toxic carcinogens. The predictivity of chromosomal aberrations as a biomarker for increased cancer risk may depend on the composition of the cohorts included in the study. The use of micronuclei as a measure of chromosomal damage has become a standard assay in both genetic toxicology testing and human biomonitoring studies. Analysis of re-sults from European cohorts indicated that subjects with cancer had a significant increase in frequency of micronuclei.
    • Specific biomarkers related to food.

      Rohrmann, Sabine; Linseisen, Jakob; Phillips, David; Georgiadis, Panagiotis; Nilsson, Robert; Kyrtopoulos, Soterios A.; Segerback, Dan; Hashibe, Mia; Boffetta, Paolo; Agudo, Antonio (The Nofer Institute of Occupational Medicine, 2006)
      The mutagenic and carcinogenic heterocyclic aromatic amines are formed from precur-sors in meat and fish at temperatures exceeding 130°C and bind covalently to DNA after metabolic activation. Heterocyclic aromatic amines in urine have short half-lives but could be used to validate intake as estimated by questionnaires. Blood protein adducts and DNA adducts from various tissues have also been analysed. No epidemiological studies have yet been conducted in humans that have examined the association between heterocyclic aromatic amine exposure assessed by means of any biomarker and the risk of cancer. Polycyclic aromatic hydrocarbons, formed by the incomplete combustion of organic matter, are ubiquitous contaminants of the environment. There have been two main approaches to measurement of polycyclic aromatic hydrocarbons in complex matrices such as food: determination of around 15–20 polycyclic aromatic hydrocarbons, including carcinogenic compounds, or measurement of benzo[a]pyrene as a surrogate for all polycyclic aromatic hydrocarbons. The first approach gives a truer picture of the overall burden of these compounds in food; however, benzo[a]pyrene, because of its carcinogenic potency in experimental animals, represents a biologically significant measure. Most types of food contain measurable levels of polycyclic aromatic hydrocarbons and dietary exposure can be a significant effect in studies designed to determine occupational exposure or exposure due to urban pollution. N-nitroso compounds, and especially alkyl nitrosamines, are well known experimental carcinogens. Nitrosamines are present in significant quantities in tobacco smoke, while dimethylnitrosamine is also found in nitrate- or nitrite-treated foods. N-nitroso com-pounds can be formed endogenously at significant levels. Most epidemiological studies attempting to associate exposure to N-nitroso compounds and various human cancers have been inconclusive. The main problem was the inadequacy of methods for estimation not only of external exposure but, more importantly, of endo-genous exposure to N-nitroso compounds. Large-scale molecular epidemiological studies to determine the carcinogenic risk associated with the widespread presence in human DNA of O6-methylguanine, which plays an important role in mutagenesis, carcinogenesis and cytotoxicity by methylating agents, are lacking due to the lack of high throughput, high sensitivity assays for this adduct. The quantitatively most important DNA alkylation lesion N-7-methylguanine is not directly premutagenic, but can undergo spontaneous depurination to form mutagenic apurinic sites. N-7-Methylguanine accumulates more in tissues from smokers than nonsmokers, indicating that this biomarker could be used as an internal dosimeter for exposure to nitrosamines. Extensive research on tobacco-specific nitrosamines has failed to provide conclusive evidence of their role in human cancer, despite their being potent rodent carcinogens. The urinary 4-nitrosomethylamino)-1-(3-pyridyl)-1-butanone metabolites 4-(methylnitrosamino)- 1-(3-pyridyl)-1-butanol and its glucuronide are absolutely specific for tobacco exposure. Significant amounts of acrylamide can occur in certain food items high in carbohydrates and amino acids after heating. Acrylamide has been classified by IARC as “probably carcinogenic to humans” and the EU has classified it as a “Category 2 carcinogen and cate-gory 2 mutagen”. The adduct of acrylamide itself to the N-terminal valine in haemoglobin and to some extent the corresponding adduct of glycidamide have been applied in human studies to assess exposure. Epidemiological investigations have not shown an increased risk from dietary exposure but larger studies of populations with more varied diets are needed; in addition data from intervention studies and on urinary metabolites and cytogenetic effects would be useful Biomarkers of alcohol may potentially be used to address the limitations of questionnaires and interviews in exposure assessment in epidemiological studies of alcohol as a risk factor for cancer. The available biomarkers differ in sensitivity, specificity, ease of assay, and the time period that they reflect and none alone is ideal; combinations of various markers may allow for finer assessment of alcohol exposures in the future. Mycotoxins are ubiquitous toxic secondary metabolites of a number of species of moulds, and occur in foods and animal feeds. Naturally occurring aflatoxins are a cause of hepato-cellular carcinoma. Most European countries have imposed limits for aflatoxin B1 in foods and for aflatoxin M1 in milk. Urinary aflatoxin B1-N-7-guanine is an excellent biomarker for studies of acute exposure but does not reflect chronic intake of aflatoxin. Aflatoxin B1-albumin adducts are currently the most widely used biomarkers of aflatoxin in epidemiological studies. Assessment of functional polymorphisms in CYP3A4 and in other enzymes involved in the activation and detoxification of aflatoxin B1 may be used as markers of susceptibility to aflatoxins. The codon 249 mutation in p53 must be used cautiously as a marker of exposure to aflatoxin until evidence has been obtained from studies measuring both aflatoxin B1 adducts and mutations in the same individuals.
    • State of validation of biomarkers of carcinogen exposure and effect. Food-chemical-specific biomarkers.

      Rohrmann, Sabine; Linseisen, Jakob; Phillips, David H.; Seidel, Albrecht; Venitt, Stan; Georgiadis, Panos; Segerback, Dan; Hashibe, Mia; Balbo, Silvia; Boffetta, Paolo; et al. (The Nofer Institute of Occupational Medicine, 2007)
    • State of validation of biomarkers of carcinogen exposure and effect. Generic biomarkers.

      Phillips, David H.; Venitt, Stan; Jonsson, Bo A.G.; Farmer, Peter; Mateuca, Raluca; Kirsch-Volders, Micheline; Loft, Steffen; Moller, Peter; Nair, Urmila; Nair, Jagadeesan (The Nofer Institute of Occupational Medicine, 2007)
    • Validation of biomarkers: application to examples.

      Gallo, Valentina; Phillips, David; Rohrman, Sabine; Linseisen, Jakob; Kovacs, Katalin; Gyorffy, Erika; Anna, Livia; Schoket, Bernadette; Loft, Steffen; Moller, Peter; et al. (The Nofer Institute of Occupational Medicine, 2007)
    • Vitamins and selenium.

      Dragsted, Lars O.; Loft, Steffen; Moller, Peter; Cook, Marcus S.; Rozalski, Rafal; Olinski, Ryszard; Linseisen, Jakob; Abbas, Sascha; Akesson, Bjorn; Bruzelius, Katharina; et al. (The Nofer Institute of Occupational Medicine, 2007-04)