Chromosomal Damage In Peripheral Lymphocytes Research Articles

Polymorphisms in BER and NER pathway genes: Effects on micronucleus frequencies among vinyl chloride-exposed workers in northern China

In this study, a group of 317 workers occupationally exposed to vinyl chloride monomer and 166 normal, unexposed referents in Shandong province (Northern China) were examined for chromosomal damage in peripheral lymphocytes using the cytokinesis-blocked micronucleus (CB-MN) assay. The exposure group (3.47±2.65)‰ showed higher micronucleus frequency than the unexposed workers (2.51±1.96)‰ (P<0.01). We explored the relationship between genetic polymorphisms of XRCC1 (−77C/T, Arg194Trp, Arg280His, Arg399Gln), APE1 Asp148Glu, XPA Ala23Gly, XPC.PAT, XPC Ala499Val, XPC Lys939Gln, XPF 5′-UTR T2063A, XPG Exon15 G-C, ERCC13′-UTR C8092A and susceptibility of chromosomal damage in all the subjects. It was found that XRCC1 −77, XRCC1 280, APE1148, XPC.PAT, XPG Exon15 G-C, and ERCC13′-UTR C8092A polymorphisms showed no significant associations with micronucleus frequency in unexposed workers. However, among the exposed workers individuals with XRCC1 (−77C/T, Arg194Trp, Arg280His, Arg399Gln) polymorphisms had a significantly higher micronucleus frequency as seen in mean frequency ratios (FR) compared with their homozygous wild-type genotypes (FR=1.21, 95% CI: 1.05–1.39; P<0.01); (FR=1.14, 95% CI: 1.00–1.38; P<0.05) and (FR=1.26, 95% CI: 1.11–1.44; P<0.01); (FR=1.23, 95% CI: 1.08–1.46; P<0.01). Four SNP sites in the nucleotide excision repair (NER) pathway were associated with susceptibility for MN frequency in either unexposed or exposed workers. Further, we observed the gene–MN association changed with exposure for XRCC1 (−77C/T, Arg194Trp, Arg280His, Arg399Gln), XPA Ala23Gly, XPC Ala499Val, XPC Lys939Gln, XPF 5′-UTR T2063A. Moreover, Individuals carrying the XPC (PAT)-(499)-(939) diplotype, PAT-CG/PAT-TG, had a higher MN frequency, compared with individuals carrying the wild-type PAT-CA/PAT-CA.

The association between genetic damage in peripheral blood lymphocytes and polymorphisms of three glutathione S-transferases in Chinese workers exposed to 1,3-butadiene

1,3-Butadiene (BD) has been classified as a human carcinogen, group I; however, the relationship between polymorphisms of glutathione S-transferases that metabolize BD and chromosomal damage is not clear. The present study used sister chromatid exchange (SCE) and cytokinesis-block micronucleus (CBMN) assays to detect chromosomal damage in peripheral lymphocytes of 44 BD-exposed workers and 39 non-exposed healthy controls. PCR and PCR-RFLP were employed to detect three known glutathione S-transferase polymorphisms GSTT1, GSTM1, and GSTP1 (Ile105Val). The data demonstrated that the micronucleus (CBMN) frequency in BD-exposed workers was significantly higher than that in controls (frequency ratio (FR)=1.48, 95% CI: 1.14–1.91, P<0.01), and the CBMN frequency was higher in workers exposed to higher cumulative BD levels (FR=1.70, 95% CI: 1.28–2.27, P<0.01). However, differences in SCE frequency were not observed (FR=1.14, 95% CI: 0.81–1.61, P>0.05). Among exposed workers, chromosomal damage was related to BD exposure levels (FR=1.35, 95% CI: 1.02–1.80, P<0.05); age, older workers exhibited higher MN frequencies than younger workers (FR=1.45, 95% CI: 1.14–1.84, P<0.05); and years of work, those with more years of work exhibited higher MN frequencies than those with fewer years (FR=1.40, 95% CI: 1.10–1.77, P<0.05). Multivariate Poisson regression analysis showed that those who carried GSTM1 (−) (FR=1.48, 95% CI: 1.14–1.92) or GSTT1 (−) (FR=1.42, 95% CI: 1.10–1.83) genotypes, and especially those who carried both (FR=2.10, 95% CI: 1.43–3.09) exhibited significantly higher MN frequencies than those carrying GSTM1 (+), GSTT1 (+) genotypes or their combination. The GSTP1 Val genotype did not affect MN frequency (P>0.05). Our results suggested that higher levels of BD exposure in the workplace resulted in increased chromosomal damage, and that polymorphisms in GSTT1 and GSTM1 genes might modulate the genotoxic effects of BD exposure. Furthermore, the GSTT1 and GSTM1 polymorphisms exhibited an additive effect. Finally, urinary DHBMA was found to provide a biomarker that correlated with airborne BD levels.

DNA repair gene polymorphisms and micronucleus frequencies in Chinese workers exposed to vinyl chloride monomer

Vinyl chloride monomer (VCM) is genotoxic and cancerogen agent. Individual variations in response to the exposure have been noticed and the variations may be due to genetic differences in the removal of VCM-DNA adducts, such as polymorphism in genes NER pathway and BER pathway. This study explores the relationship between genetic polymorphism of seven genes within the NER pathway (XPA, XPD, XPC, XPG, XPF, and ERCC1) and BER pathway (APE1), and susceptibility to chromosomal damage after exposure to VCM. One hundred and eighty workers occupationally exposed to VCM and 43 unexposed controls were investigated. Chromosome damage in peripheral lymphocytes was measured by the cytokinesis-blocked micronucleus assay. PCR-RFLP technique was applied to detect polymorphisms of the seven genes. The influence of genotype, age, gender, cumulative exposure dose, alcohol consumption, and smoking status on the frequencies of MN was determined using univariate and multiple Poisson regression analyses. We found XPA A23G variant workers had significantly higher MN frequencies than those from the wild-type homozygous counterparts (P = 0.01). Those with the variant XPD Lys751Gln genotype had marginally higher MN frequencies (P = 0.07). On the other hand, XPC PAT and XPF 5'-UTR T2063A variant workers had significantly lower MN frequencies compared with those from their wild-type homozygous counterparts (P = 0.04 and P = 0.004, respectively). Our findings suggest that XPC PAT, XPD Lys751Gln, XPA A23G and XPF 5'-UTR T2063A contribute to the level of chromosome damage in occupational exposure to VCM in Chinese population.

Cytoprotective effect of honey against chromosomal breakage in fanconi anemia patients in vitro

BACKGROUND:Natural honey is widely used all over the world as a complementary and alternative medicine in various disorders including Fanconi anemia (FA). FA is a rare genetic chromosomal instability syndrome caused by impairment of DNA repair and reactive oxygen species (ROS) imbalance. This disease is also related to bone marrow failure and cancer. The aim of this study was to evaluate the cytoprotective effect of honey on mitomycin C (MMC-) induced chromosomal damage in peripheral lymphocytes from FA patients.MATERIALS AND METHODS:Treatment of these complications with alkylation agents MMC may enhance chromosomal breakage. We have evaluated the effect of honey on MMC- induced chromosomal breakage in FA blood cells using chromosomal breakage assay. The basal chromosomal breakage count was higher among FA patients than healthy subjects.RESULTS:The addition of MMC alone gave a significantly higher of chromosomal breakage in FA patients than control group (P < 0.0001). Pre- treatment with honey significantly inhibited breakage induced by MMC in FA patients by its antioxidant effect.CONCLUSION:Honey can prevent MMC- induced chromosomal breakage by its antioxidant effect.

Genetic Polymorphisms in Metabolizing Enzymes and Susceptibility of Chromosomal Damage Induced by Vinyl Chloride Monomer in a Chinese Worker Population

To evaluate whether polymorphisms in metabolizing enzymes contributed to susceptibility of chromosomal damage induced by vinyl chloride monomer (VCM). Cytokinesis block micronucleus test was performed on 185 VCM-exposed workers and 41 control subjects to detect chromosomal damage in peripheral lymphocytes. The polymerase chain reaction and restriction fragment length polymorphism technique was applied to detect polymorphisms of GSTT1, GSTM1, GSTP1G/A, CYP2E1G/C, and CYP2D6G/C. Poisson regression analysis was performed. Sex, age, VCM exposure, GSTP1, and CYP2E1 genotype can influence chromosomal damage. There was a 1.51-fold increased micronucleus frequency for GSTP1GG genotypes individuals compared with those GSTP1AA/GA genotype individuals (P < 0.05), the effect of polymorphism in CYP2E1 gene was more pronounced for allele C compared with allele G (P < 0.05). Polymorphisms of GSTP1G/A and CYP2E1G/C, which are potential susceptibility biomarkers of chromosomal damage in VCM-exposed worker.

Micronucleus Occurrence Related to Base Excision Repair Gene Polymorphisms in Chinese Workers Occupationally Exposed to Vinyl Chloride Monomer

To evaluate whether base excision repair gene polymorphisms contributed to susceptibility of chromosomal damage induced by vinyl chloride monomer (VCM). Cytokinesis block micronucleus test was performed on 185 VCM-exposed workers to detect chromosomal damage in peripheral lymphocytes. The PCR-restriction fragment length polymorphism technique was applied to detect polymorphisms of TDG, PARP1, and APE1 genes. Univariate and multivariate Poisson regression analysis was performed. There was a 1.198-fold increased micronucleus frequency for individuals carrying TDG 199Gly/Ser + Ser/Ser genotypes compared with those carrying Gly/Gly genotype (P < 0.05). Individuals with the combined genotypes of TDG 199Gly/Ser + Ser/Ser and APE1 64Ile/Val + Val/Val had a significantly increased micronucleus frequency compared with those carrying wild-type genotypes for both genes. VCM-exposed workers carrying TDG 199Gly/Ser + Ser/Ser genotypes were susceptible to chromosomal damage. A combination of TDG Gly199Ser and APE1 Ile64Val polymorphisms may modify the risk of chromosomal damage.

Suboptimal DNA Repair Capacity Predisposes Coke-Oven Workers To Accumulate More Chromosomal Damages in Peripheral Lymphocytes

DNA repair is an essential mechanism for cells to maintain their genomic integrity under endogenous or exogenous assault. Reduced DNA repair capacity (DRC) is associated with increased risk for several environmentally related cancers. The micronucleus in peripheral lymphocytes has been validated as a biomarker of chromosomal damage, increasing cancer risk in human populations. We hypothesized that suboptimal DRC is associated with the increase in chromosomal damage among 94 coke-oven workers and 64 noncoke-oven controls. DRC was evaluated in isolated lymphocytes by comet assay. Chromosomal damage in peripheral lymphocytes was detected by cytokinesis-block micronucleus assay. Four common coding single nucleotide polymorphisms in the XRCC1 gene were genotyped. Coke-oven workers have significantly increased urinary 1-hydroxypyrene (9.0; 6.8-11.7 microg/L versus 1.5, 1.3-1.7 microg/L; P<0.01) and micronucleus frequency (7.4 per thousand+/-4.3 per thousand versus 3.0 per thousand+/-3.0 per thousand; P<0.01), and decreased DRC (55.9%+/-16.4% versus 63.6%+/-18.5%; P<0.01) compared with controls. Significant correlations between DRC and micronucleus frequency were found in coke-oven workers (r=-0.32; P<0.01; n = 94) and all study subjects (r=-0.32; P<0.001; n=158) but not in controls (r=-0.21; P=0.11; n=64). Variants of the Arg399Gln polymorphism were associated with a decreased DRC in both coke-oven workers (51.6%+/-16.1% versus 60.6%+/-15.7%; P<0.01) and controls (59.1%+/-18.5% versus 68.4%+/-17.5%; P=0.04). The complicated interrelationship of these multiple biomarkers was also identified by path analysis. These findings should facilitate developing a biomarker-based risk assessment model for lung cancer in this occupational population.

No Chromosomal Damage Seen From ADHD Medications

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessNo Chromosomal Damage Seen From ADHD MedicationsJun YanJun YanSearch for more papers by this authorPublished Online:2 Jan 2009https://doi.org/10.1176/pn.44.1.0018aStimulants commonly used to treat attention-deficit/hyperactivity disorder (ADHD), specifically methylphenidate and amphetamine, do not cause chromosomal damages in circulating white blood cells, a study in the December 2008 Journal of the American Academy of Child and Adolescent Psychiatry finds.A study published in the December 18, 2005, Cancer Letters presented evidence of an increased frequency of three types of chromosomal damage in peripheral lymphocytes in 12 children after they had taken methylphenidate for three months. These types of chromosomal damage indicate DNA damage and structural changes to chromosomes and are associated with an increased risk of cancer.Since this alarming finding, several smaller human, in vitro, and animal studies were published that failed to replicate the stimulant-associated chromosomal damage seen in the original study.The new study was conducted with a methodology similar to the original study, but expanded the number of subjects and included mixed amphetamine salts (MAS) in addition to methylphenidate. Sixty-three children aged 6 to 12 with a DSM-IV diagnosis of ADHD were randomly assigned to open-label treatment with either methylphenidate or MAS for three months. None of them had taken stimulants before.The researchers found no significant increase from baseline to the end of the three-month treatment in any of the types of chromosomal damage reported in the previous study in either patients who took methylphenidate (n=25) or those who took MAS (n=22). In addition to these 47 subjects, 14 discontinued study participation prematurely for various reasons, and two were switched to different medications by their physicians and completed three months of treatment. No significant association between treatment and chromosomal damage was found in these individuals.The researchers examined the participants' blood samples, taken before and after the three months of stimulant treatment, for any chromosomal damage in lymphocytes. The percentages of cells with the damage at both time points as well as between the methylphenidate and the MAS groups were compared. No significant difference was seen between the two groups.The study was conducted at the Duke University Medical Center by Kristine Witt, M.S., and colleagues affiliated with the National Institute of Child Health and Human Development (NICHD) and the National Toxicology Program of the National Institute of Environmental Health Sciences (NIEHS). NICHD and NIEHS, both divisions of the National Institutes of Health, provided funding for the study.“These results add to the accumulating evidence that therapeutic levels of methylphenidate do not induce cytogenetic damage in humans,... and amphetamine-based products do not pose a risk for cytogenetic damage in children,” the authors concluded.An abstract of “Methylphenidate and Amphetamine Do Not Induce Cytogenetic Damage in Lymphocytes of Children With ADHD” is posted at<www.jaacap.com/pt/re/jaacap/abstract.00004583-200812000-00006.htm>.▪ ISSUES NewArchived

Sensitivity to cisplatin-induced mutations and elevated chromosomal aberrations in lymphocytes from sickle cell disease patients

Sickle cell disease (SCD) is an inherited disorder caused by a single nucleotide substitution in the beta-globin gene. The clinical heterogeneity observed in SCD patients has been attributed to environmental and genetic factors. The patients are subjected to increased oxidative stress, particularly during vaso-occlusive crises and acute chest pain. Another possible cause of oxidative stress in SCD is the high concentration of iron in the patients' plasma. The increase in oxidative stress could be a relevant risk factor for mutagenesis and carcinogenesis. Studies on the frequency of basal chromosomal aberrations in cultured lymphocytes from SCD patients have not been reported so far. In order to contribute to the understanding of the role of the different biomarkers and their relationship with the extremely variable clinical manifestation of SCD, we investigated the frequency of chromosome damage in peripheral lymphocytes from sickle cells patients and healthy controls. We found an increased frequency of chromosome damage and percentage of aberrant metaphases in these patients when compared with control subjects, even at basal values (p<0.05). In the cytogenetic sensitivity assay, the results showed that these patients presented a marked decrease in the mitotic index values compared with healthy controls. Cisplatin-induced chromosomal damage in lymphocytes from these patients was significantly higher than the frequency measured in healthy controls. The results obtained in the present study showed that more investigations are needed in order to elucidate the susceptibility to genomic instability of SCD patients.

Analysis of spontaneous and bleomycin-induced chromosome damage in peripheral lymphocytes of long-haul aircrew members from Argentina

Spontaneous and bleomycin (BLM)-induced chromosomal aberrations in G0 and G2 stages of the cell cycle have been analyzed in peripheral lymphocytes of 21 long-haul aircrew members from Argentina in order to assess BLM-induced clastogenesis as a first approach to determine the DNA repair capacity and thereby the susceptibility to environmental cancers in aircrew. The possibility that occupational exposure of flight personnel to cosmic radiation can induce an adaptive response in their peripheral lymphocytes that can be detected by a subsequent in vitro treatment with BLM was also investigated. For comparison, aberrations were also scored in the lymphocytes of 15 healthy volunteers matched by age, health, sex, drinking and smoking habits to the flight personnel group. Aircrew exhibited a higher frequency of spontaneous dicentrics and ring chromosomes than the control population ( p < 0.05). BLM sensitivity test showed that aircrew and controls are equally sensitive to BLM G2 clastogenic effects, since both groups exhibited a similar frequency of chromatid breaks per cell ( p > 0.05). However, the aircrew sampled population was almost two times more sensitive to BLM G0 clastogenic effects than controls ( p < 0.05). Therefore, our data suggest that chronic exposure of aircrew to cosmic radiation increases the in vitro chromosomal sensitivity of their peripheral lymphocytes to BLM (at least in the G0 stage of the cell cycle), and that occupational exposure of flight personnel to cosmic radiation does not induce an adaptive response to this radiomimetic compound. Our results justify further studies aimed at determine if those aircrew members hypersensitive to BLM are more prone to develop environmental cancer than BLM-insensitive individuals.

Analysis of chromosome damage in circulating lymphocytes of radiological workers affected by thyroid nodules

The aim of our study was to assess whether or not thyroid nodularity in combination with occupational exposure to low levels of ionising radiation would be correlated with chromosome damage in peripheral lymphocytes. Conventional chromosome-aberration analysis was performed on a group of 92 hospital workers with or without thyroid nodules. On the basis of measurements of their exposure levels, the workers were classified into a low (mean total level = 0.03 mSv), medium (mean total level = 1.04 mSv) or high (mean total level = 8.60 mSv) exposure category. Our results indicate that among workers with thyroid nodules, the high-exposed workers showed significantly higher levels of both total (2.35 ± 0.34 per 100 cells) and chromosome-type aberrations (1.46 ± 0.20 per 100 cells) than medium-exposed (0.98 ± 0.42 and 0.68 ± 0.25 per 100 cells, respectively) or low-exposed workers (1.11 ± 0.29 and 0.58 ± 0.17 per 100 cells, respectively). Workers without thyroid nodules had comparable frequencies of chromosome aberrations among the three exposure categories. To our knowledge, this is the first study revealing a slight, but significant increase of chromosome damage in peripheral lymphocytes from hospital workers who developed thyroid nodules under conditions of occupational exposure to radiation well below the threshold limit for the workplace. The existence of a possible association between chromosome aberrations and development of thyroid nodularity will be discussed.

A polymorphism of the methionine synthase reductase gene increases chromosomal damage in peripheral lymphocytes in smokers

The cytogenetic effects of cigarette smoke has been evaluated as one of many potential confounders in a large number of biomonitoring studies of occupationally or environmentally exposed populations and control subjects. Despite the well-known presence of carcinogens in the cigarette smoke, the results in the scientific literature linking smoking habits to micronuclei (MN) frequency, one of the cytogenetic markers, are rather controversial. Here, we investigated the relationships among MN frequency, smoking habits and five folate metabolic enzyme gene polymorphisms ( MTHFR C677T and A1298C, MTR A2756G, MTRR A66G and TYMS 3′UTR) in 132 healthy Japanese men who were non-habitual drinkers. In never- and former-smokers, no statistically significant differences in the mean MN frequencies were observed according to the five folate metabolic enzyme gene polymorphisms. In current-smokers, however, subjects with the AA genotype for MTRR had a significantly higher mean MN frequency than the AG genotypes for MTRR ( p < 0.05). Furthermore, among subjects with the AA genotype for MTRR, current-smokers were found to have a significantly higher mean MN frequency than never- and former-smokers ( p < 0.05). To further characterize this association, we stratified the smoking status into five groups: non-smokers (never-smokers and former-smokers), 1–10 cigarettes/day, 11–20 cigarettes/day, 21–30 cigarettes/day and ≥31 cigarettes/day. There was an overall trend for the mean MN frequency in subjects with the MTRR AA genotype to increase as the number of cigarettes smoked per day increased ( p < 0.01, Jonckheere–Terpstra test). The results of our preliminary study suggest that the MTRR AA genotype acts to increase the MN frequency resulting from cigarette smoking. Therefore, studies on human genotoxicity based on cytogenetic markers of MN should take into account both the MTRR polymorphism and the potential confounding effect of smoking, although these preliminary findings need to be validated in larger populations because of the relatively small sample size.

Chromosome damage in peripheral lymphocytes of sheep induced by chlorine in drinking water

The potential of chromosomal damage associated with the effects of chlorine in drinking water was evaluated using chromosome aberrations and micronuclei as cytogenetic endpoints in the lymphocytes of peripheral blood of ewe lambs. The study assessed the in vivo effects of high chlorine doses (1.8 mg l − 1, based on Savo-Super disinfectant) in drinking water on the peripheral lymphocytes of sheep after 30 days. The frequency of aberrant cells (AB.C.) in the experimental and control groups was 31.80 ± 13.68% AB.C. and 4.50 ± 2.07% AB.C. respectively, and the increased AB.C. in the treated group was highly significant (P = < 0.001). In the experimental group chromatid breaks (26.20 ± 10.47%) and gaps (24.20 ± 13.94%) were the dominant types of aberrations, but statistically significant chromosome gaps and exchanges were also present. The frequency of micronuclei in peripheral lymphocytes of sheep in the control group was 21.17 ± 4.36 per 1,000 binucleated cells and 64.20 ± 22.51 per 1,000 binucleated cells in the experimental group. A significant increase in the frequency of micronuclei in peripheral lymphocytes of sheep was observed between the two groups (P = 0.001).

Radiosensitivity of ataxia telangiectasia and Nijmegen breakage syndrome homozygotes and heterozygotes as determined by three-color FISH chromosome painting.

A three-color chromosome painting technique was used to examine the spontaneous and radiation-induced chromosomal damage in peripheral lymphocytes and lymphoblastoid cells from 11 patients with ataxia telangiectasia (AT) and from 14 individuals heterozygous for an AT allele. In addition, cells from two homozygous and six obligate heterozygous carriers of mutations in the Nijmegen breakage syndrome gene (NBS) were investigated. The data were compared to those for chromosome damage in 10 unaffected control individuals and 48 cancer patients who had not yet received therapeutic treatment. Based on the well-documented radiation sensitivity of AT and NBS patients, it was of particular interest to determine whether the FISH painting technique used in these studies allowed the reliable detection of an increased sensitivity to in vitro irradiation of cells from heterozygous carriers. Peripheral blood lymphocytes and lymphoblastoid cells from both the homozygous AT and NBS patients showed the highest cytogenetic response, whereas the cells from control individuals had a low number of chromosomal aberrations. The response of cells from heterozygous carriers was intermediate and could be clearly differentiated from those of the other groups in double-coded studies. AT and NBS heterozygosity could be distinguished from other genotypes by the total number of breakpoints per cell and also by the number of the long-lived stable aberrations in both AT and NBS. Only AT heterozygosity could be distinguished by the fraction of unstable chromosome changes. The slightly but not significantly increased radiosensitivity that was found in cancer patients was apparently due to a higher trend toward rearrangements compared to the controls. Thus the three-color painting technique presented here proved to be well suited as a supplement to conventional cytogenetic techniques for the detection of heterozygous carriers of these diseases, and may be superior method.

Chronic long-term nitrate therapy: possible cytogenetic effect in humans?

Nitrates act as donors of nitric oxide (NO), a molecule with a recognized potential for genotoxicity. In order to assess whether chronic long-term nitrate therapy may increase genotoxicity, we evaluated chromosomal damage in peripheral lymphocytes of 27 ischaemic patients undergoing chronic nitrate treatment for vertical line4 years (7.9 +/- 3.1, mean +/- SD) and 18 age- and sex-matched subjects without any previous nitrate treatment. At the same time, after treatment in vitro with 0-20 microM sodium nitroprusside as NO donor, micronucleus induction and cell proliferation were also evaluated using blood from six different healthy donors. The results showed that the frequency of structural chromosomal aberrations was not significantly higher in the drug-treated group than the control [2.1 +/- 1.4 versus 1.6 +/- 1.2 (mean +/- SD); P = 0.23]. The frequency of micronucleated lymphocytes was higher in the nitrate group than in the control group (6.5 +/- 4.6 versus 3.5 +/- 2.9, P=0.01). In vitro treatment indicated a dose-dependent increase in the frequency of micronucleated lymphocytes with increasing SNP concentrations. Cytotoxicity and cell cycle delay, with a statistically significant difference with respect to control culture, were also observed. Our results suggest a possible genotoxic activity of nitrate therapy. Further studies focusing on the possible link between nitrate therapy and genotoxicity are warranted at this point.

Cytogenetic damage after 131-iodine treatment for hyperthyroidism and thyroid cancer. A study using the micronucleus test.

To detect the incidence and persistence of potential chromosome damage induced by iodine-131 therapy, we applied the cytokinesis-block micronucleus assay to peripheral blood lymphocytes from hyperthyroidism and thyroid cancer patients treated with 131I. Two groups of patients were evaluated in a longitudinal study; one group was composed of 47 hyperthyroid patients and the other of 39 thyroid cancer patients. In the hyperthyroidism group, the micronuclei frequency was determined before 131I therapy and 1 week, 1 month and 3 months after it. Furthermore, an additional sample was taken from a subgroup of 17 hyperthyroidism patients 6 months after treatment. In the thyroid cancer group, the analysis was also conducted over time, and four samples were studied: before treatment and 1 week, 6 months and 1 year later. Simultaneously, a cross-sectional study was performed with 70 control subjects and 54 thyroid cancer patients who had received the last therapeutic dose 1-6 years before the present study. In the hyperthyroidism group a significant increase in the micronuclei average was found over time. In the sample obtained 6 months after therapy, the micronuclei mean frequency was practically the same as in the sample taken 3 months before. In the thyroid cancer group a twofold increase in the frequency of micronuclei was seen 1 week after therapy. Although this value decreased across time, the micronuclei frequency obtained 1 year after 131I therapy remained higher than the value found before it. Concerning the data from the cross-sectional study, a significant increase in the frequency of micronuclei was detected in the subgroup of thyroid cancer patients treated between 1 and 3 years before the current study. These results indicate that exposure to 131I therapy induces chromosome damage in peripheral lymphocytes and that the cytokinesis-block micronucleus assay is sensitive enough to detect the genetic damage by exposure to sufficiently high levels of radiation from internal radioactive sources.

Animals as sentinels of human health hazards of environmental chemicals.

A workshop titled "Using Sentinel Species Data to Address the Potential Human Health Effects of Chemicals in the Environment," sponsored by the U.S. Army Center for Environmental Health Research, the National Center for Environmental Assessment of the EPA, and the Agency for Toxic Substances and Disease Registry, was held to consider the use of sentinel and surrogate animal species data for evaluating the potential human health effects of chemicals in the environment. The workshop took a broad view of the sentinel species concept, and included mammalian and nonmammalian species, companion animals, food animals, fish, amphibians, and other wildlife. Sentinel species data included observations of wild animals in field situations as well as experimental animal data. Workshop participants identified potential applications for sentinel species data derived from monitoring programs or serendipitous observations and explored the potential use of such information in human health hazard and risk assessments and for evaluating causes or mechanisms of effect. Although it is unlikely that sentinel species data will be used as the sole determinative factor in evaluating human health concerns, such data can be useful as for additional weight of evidence in a risk assessment, for providing early warning of situations requiring further study, or for monitoring the course of remedial activities. Attention was given to the factors impeding the application of sentinel species approaches and their acceptance in the scientific and regulatory communities. Workshop participants identified a number of critical research needs and opportunities for interagency collaboration that could help advance the use of sentinel species approaches.

A Nordic data base on somatic chromosome damage in humans

Analyses of cytogenetic damage — chromosome aberrations (CA), micronuclei (MN), and sister-chromatid exchange (SCE) — are used to assess genotoxic exposure, on the supposition that higher levels of chromosome damage in peripheral lymphocytes reflect increased cancer risk. We attempt to test this hypothesis prospectively, by relating levels of cytogenetic damage to subsequent cancer morbidity in a cohort comprising 3190 subjects. All these subjects have been analyzed previously (1970–1988) for CA, MN, and/or SCE in studies of occupational and environmental exposure. The present paper describes the data base and assesses how the potential confounders smoking habits, sex, and age influence CA, MN, and SCE levels. Ten Nordic laboratories contributed data. In the present analyses, these data were treated separately to avoid the effects of interlaboratory differences. Point estimates from multiple regression analyses indicate that smoking may increase CA frequencies by up to 10–20% and SCE means by 5–8%, but that it has no effect on MN frequencies. Women had higher CA, MN, and SCE levels than men, but the sex effect was generally smaller than the effect of smoking. Age was positively associated with cytogenetic damage. Compared to the sex effect, the effect of a 10-year age increase was similar on CA, but less, 1–3%, on SCE. The amount of variation explained by the potential confounders taken together was generally low, often less than 20%. Thus, other still unknown factors must be the major sources of CA, MN, and SCE variability.

Induction of mitotic micronuclei by X-ray contrast media in human peripheral lymphocytes

In vitro and in vivo cytogenetic effects of X-ray contrast media (CM) were determined by scoring micronuclei (MN) in 72-h cultures of human peripheral lymphocytes. Both ionic (sodium meglumine diatrizoate, methylglucamine diatrizoate, and sodium meglumine ioxaglate and nonionic CM (iosimide, iopromide, iohexol and iotrolan) were able to induce MN in lymphocytes. Based upon their calculated percent probabilities for MN induction, these agents could be ranked in their decreasing order of probability, as iosimide > sodium meglumine ioxaglate > iohexol > sodium meglumine diatrizoate > iopromide > methylglucamine diatrizoate > iotrolan. Stepwise logistic regression analysis of the data indicated that the frequency of MN in CM-exposed lymphocyte cultures was significantly higher than the frequency of MN in control cultures ( P < 0.001). In clinical studies where 14 patients were injected with an ionic CM methylglucamine diatrizoate, lymphocyte cultures from 10 patients showed higher frequencies of MN. The differences between pre- and post-CM counts of MN were significant in a Mann-Whitney U test ( P < 0.05). The effect of X-irradiation on MN formation in lymphocytes was separately determined and was found to be insignificant. These results indicate that irrespective of ionic and osmolality differences, X-ray contrast agents are capable of producing chromosomal damage in peripheral lymphocytes. Further studies are required to establish molecular mechanisms in the observed cytogenetic effects of CM in cell cultures.

Chromosome Damage in Peripheral Lymphocytes from American Thorium Workers

Chromosome Damage in Peripheral Lymphocytes from American Thorium Workers