• Biomarkers of exposure, effect, and susceptibility in workers exposed to nitrotoluenes.

      Sabbioni, Gabriele; Jones, Christopher R.; Sepai, Ovnair; Hirvonen, Ari; Norppa, Hannu; Järventaus, Hilkka; Glatt, Hansruedi; Pomplun, Doreen; Yan, Huifang; Brooks, Lance R.; et al. (2006-03)
      Nitrotoluenes, such as 2-nitrotoluene, 2,4-dinitrotoluene (24DNT), and 26DNT, are carcinogenic in animal experiments. Humans are exposed to such chemicals in the workplace and in the environment. It is therefore important to develop methods to biomonitor people exposed to nitrotoluenes to prevent the potential harmful effects. For the present study, workers exposed to high levels of these chemicals were investigated. The external dose (air levels), the internal dose (urine metabolites), the biologically effective dose [hemoglobin (Hb) adducts and urine mutagenicity], and biological effects (chromosomal aberrations and health effects) were determined. Individual susceptibility was assessed by determining genetic polymorphisms of enzymes assumed to function in nitrotoluene metabolism, namely glutathione S-transferases (GSTM1, GSTT1, GSTP1), N-acetyltransferases (NAT1, NAT2), and sulfotransferases (SULT1A1, SULT1A2). The levels of urinary metabolites did not correlate with the air levels. The urinary mutagenicity levels determined in a subset of workers correlated with the levels of a benzylalcohol metabolite of DNT. The Hb-adducts correlated with the urine metabolites but not with the air levels. The frequency of chromosomal aberrations (gaps included) was increased (P < 0.05) in the exposed workers in comparison with a group of factory controls and correlated with the level of 24DNT Hb-adducts in young subjects (<31 years). The GSTM1-null genotype was significantly more prevalent in the controls than in the exposed group, which probably reflected an elevated susceptibility of the GSTM1-null genotype to adverse health effects of DNT exposure, such as nausea (odds ratio, 8.8; 95% confidence interval, 2.4-32.2). A statistically significant effect was seen for SULT1A2 genotype on a 24DNT Hb-adduct; GSTP1 genotype on a 2,4,6-trinitrotoluene Hb-adduct; and SULT1A1, SULT1A2, NAT1, GSTT1, and GSTP1 genotypes on chromosomal aberrations in the exposed workers.
    • Selenium, apoptosis, and colorectal adenomas.

      Connelly-Frost, Alexandra; Poole, Charles; Satia, Jessie A.; Kupper, Lawrence L.; Millikan, Robert C.; Sandler, Robert S. (2006-03)
      BACKGROUND: Selenium is an essential trace element found in cereals, wheat, dairy products, meat, and fish. This micronutrient may prevent carcinogenesis through several biochemical pathways; one suggested pathway is enhanced apoptosis. OBJECTIVES: The relation between selenium and colorectal adenomas was evaluated because the colorectal adenoma is the established precursor lesion of most colorectal cancers. Apoptosis was a pathway of interest because decreased apoptosis has been associated with an increased prevalence of adenomas. Our objectives were as follows: to investigate the association between (a) selenium and colorectal adenomas and (b) selenium and apoptosis. METHODS: The study population was assembled for the Diet and Health Study III (n = 803), a cross-sectional study conducted at the University of North Carolina Hospital (Chapel Hill, NC). There were 451 participants in the analysis of selenium and adenoma prevalence and 351 participants in the analysis of selenium and apoptosis. Selenium was measured from serum collected at the time of colonoscopy. Apoptosis was measured in biopsies from normal rectal epithelium obtained during the colonoscopy procedure. RESULTS: Participants in the highest fifth of serum selenium were less likely to have adenomas in comparison with those in the lowest fifth (prevalence ratio, 0.6; 95% confidence interval, 0.4-1.1). Selenium and apoptosis (>2.76 cells per crypt) were not strongly related, but results collectively suggested a roughly inverse association. CONCLUSIONS: High selenium was associated with a reduced prevalence of colorectal adenomas. Apoptosis, however, did not seem to be the mechanism by which selenium was related to adenoma prevalence in our data.