State of the Science in Dried Blood Spots.

BACKGROUND: Advancements in the quality and availability of highly sensitive analytical instrumentation and methodologies have led to increased interest in the use of microsamples. Among microsamples, dried blood spots (DBS) are the most well-known. Although there have been a variety of review papers published on DBS, there has been no attempt at describing the full range of analytes measurable in DBS, or any systematic approach published for characterizing the strengths and weaknesses associated with adoption of DBS analyses. CONTENT: A scoping review of reviews methodology was used for characterizing the state of the science in DBS. We identified 2018 analytes measured in DBS and found every common analytic method applied to traditional liquid samples had been applied to DBS samples. Analytes covered a broad range of biomarkers that included genes, transcripts, proteins, and metabolites. Strengths of DBS enable its application in most clinical and laboratory settings, and the removal of phlebotomy and the need for refrigeration have expanded biosampling to hard-to-reach and vulnerable populations. Weaknesses may limit adoption in the near term because DBS is a nontraditional sample often requiring conversion of measurements to plasma or serum values. Opportunities presented by novel methodologies may obviate many of the current limitations, but threats around the ethical use of residual samples must be considered by potential adopters. SUMMARY: DBS provide a wide range of potential applications that extend beyond the reach of traditional samples. Current limitations are serious but not intractable. Technological advancements will likely continue to minimize constraints around DBS adoption.

Polycyclic aromatic hydrocarbons and childhood asthma.

Asthma is the most common chronic illness in children living in developed countries and the leading cause of childhood hospitalization and school absenteeism. Prevalence rates of asthma are increasing and show disparities across gender, geographic regions, and ethnic/racial groups. Common risk factors for developing childhood asthma include exposure to tobacco smoke, previous allergic reactions, a family history of asthma, allergic rhinitis or eczema, living in an urban environment, obesity and lack of physical exercise, severe lower respiratory tract infections, and male gender. Asthma exacerbation in children can be triggered by a variety of factors, including allergens (e.g., pollen, dust mites, and animal dander), viral and bacterial infections, exercise, and exposure to airway irritants. Recent studies have shown that exposure to polycyclic aromatic hydrocarbons (PAHs), a major component of fine particulate matter from combustion sources, is also associated with onset of asthma, and increasing asthmatic symptoms. In this paper, we review sources of childhood PAH exposure and the association between airborne PAH exposure and childhood asthma prevalence and exacerbation.

DNA repair gene variants in relation to overall cancer risk: a population-based study.

The hypothesis that germ-line polymorphisms in DNA repair genes influence cancer risk has previously been tested primarily on a cancer site-specific basis. The purpose of this study was to test the hypothesis that DNA repair gene allelic variants contribute to globally elevated cancer risk by measuring associations with risk of all cancers that occurred within a population-based cohort. In the CLUE II cohort study established in 1989 in Washington County, MD, this study was comprised of all 3619 cancer cases ascertained through 2007 compared with a sample of 2296 with no cancer. Associations were measured between 759 DNA repair gene single nucleotide polymorphisms (SNPs) and risk of all cancers. A SNP in O(6)-methylguanine-DNA methyltransferase, MGMT, (rs2296675) was significantly associated with overall cancer risk [per minor allele odds ratio (OR) 1.30, 95% confidence interval (CI) 1.19-1.43 and P-value: 4.1 × 10(-8)]. The association between rs2296675 and cancer risk was stronger among those aged ≤54 years old than those who were ≥55 years at baseline (P-for-(interaction) = 0.021). OR were in the direction of increased risk for all 15 categories of malignancies studied (P < 0.0001), ranging from 1.22 (P = 0.42) for ovarian cancer to 2.01 (P = 0.008) for urinary tract cancers; the smallest P-value was for breast cancer (OR 1.45, P = 0.0002). The results indicate that the minor allele of MGMT SNP rs2296675, a common genetic marker with 37% carriers, was significantly associated with increased risk of cancer across multiple tissues. Replication is needed to more definitively determine the scientific and public health significance of this observed association.

Variation in PAH-related DNA adduct levels among non-smokers: the role of multiple genetic polymorphisms and nucleotide excision repair phenotype.

Polycyclic aromatic hydrocarbons (PAHs) likely play a role in many cancers even in never-smokers. We tried to find a model to explain the relationship between variation in PAH-related DNA adduct levels among people with similar exposures, multiple genetic polymorphisms in genes related to metabolic and repair pathways, and nucleotide excision repair (NER) capacity. In 111 randomly selected female never-smokers from the Golestan Cohort Study in Iran, we evaluated 21 SNPs in 14 genes related to xenobiotic metabolism and 12 SNPs in eight DNA repair genes. NER capacity was evaluated by a modified comet assay, and aromatic DNA adduct levels were measured in blood by32P-postlabeling. Multivariable regression models were compared by Akaike's information criterion (AIC). Aromatic DNA adduct levels ranged between 1.7 and 18.6 per 10(8) nucleotides (mean: 5.8 ± 3.1). DNA adduct level was significantly lower in homozygotes for NAT2 slow alleles and ERCC5 non-risk-allele genotype, and was higher in the MPO homozygote risk-allele genotype. The sum of risk alleles in these genes significantly correlated with the log-adduct level (r = 0.4, p < 0.001). Compared with the environmental model, adding Phase I SNPs and NER capacity provided the best fit, and could explain 17% more of the variation in adduct levels. NER capacity was affected by polymorphisms in the MTHFR and ERCC1 genes. Female non-smokers in this population had PAH-related DNA adduct levels three to four times higher than smokers and occupationally-exposed groups in previous studies, with large inter-individual variation which could best be explained by a combination of Phase I genes and NER capacity.

Polycyclic aromatic hydrocarbons: determinants of urinary 1-hydroxypyrene glucuronide concentration and risk of colorectal cancer in the Shanghai Women's Health Study.

BACKGROUND: Associations between polycyclic aromatic hydrocarbons (PAHs) and colorectal cancer have been reported previously but few studies have characterized PAH exposure using biological measurements. We evaluated colorectal cancer risk in relation to urinary concentration of 1-hydroxypyrene glucuronide (1-OHPG), a polycyclic aromatic hydrocarbon (PAH) metabolite, and assessed determinants of PAH exposure among controls in the Shanghai Women's Health Study (SWHS). METHODS: Concentrations of 1-OHPG were measured in spot urine samples collected from 343 colorectal cancer cases and 343 individually matched controls. Questionnaires were administered to collect information on demographic characteristics and reported exposures. Odds ratios were calculated for risk of colorectal cancer in relation to quartiles of urinary 1-OHPG concentration. Potential determinants of natural log-transformed urinary 1-OHPG concentration were evaluated among a combined sample of controls from this study and another nested case-control study in the SWHS (N(total)=652). RESULTS: No statistically significant differences in risk of colorectal cancer by urinary 1-OHPG levels were observed. Among controls, the median (interquartile range) urinary 1-OHPG concentration was 2.01 pmol/mL (0.95-4.09). Active and passive smoking, using coal as a cooking fuel, eating foods that were cooked well done, and recent consumption of fried dough (e.g., yóutiáo) were associated with elevated levels of 1-OHPG, though only active smoking and fried dough consumption achieved statistical significance in multivariate analyses. CONCLUSIONS: This study does not provide evidence of an association between urinary levels of 1-OHPG and risk of colorectal cancer among women. Several environmental and dietary sources of PAH exposure were identified. Overall, the levels of 1-OHPG in this population of predominantly non-smoking women were considerably higher than levels typically observed among non-smokers in Europe, North America, and other developed regions.

A population-based study of DNA repair gene variants in relation to non-melanoma skin cancer as a marker of a cancer-prone phenotype.

For unknown reasons, non-melanoma skin cancer (NMSC) is associated with increased risk of other malignancies. Focusing solely on DNA repair or DNA repair-related genes, this study tested the hypothesis that DNA repair gene variants contribute to the increased cancer risk associated with a personal history of NMSC. From the parent CLUE II cohort study, established in 1989 in Washington County, MD, the study consisted of a cancer-free control group (n 5 2296) compared with three mutually exclusive groups of cancer cases ascertained through 2007: (i) Other (non-NMSC) cancer only (n 5 2349); (ii) NMSC only (n 5 694) and (iii) NMSC plus other cancer (n 5 577). The frequency of minor alleles in 759 DNA repair gene single nucleotide polymorphisms (SNPs) was compared in these four groups. Comparing those with both NMSC and other cancer versus those with no cancer, 10 SNPs had allelic trend P-values <0.01. The two top-ranked SNPs were both within the thymine DNA glycosylase gene (TDG). One was a non-synonymous coding SNP (rs2888805) [per allele odds ratio (OR) 1.40, 95% confidence interval (CI) 1.16-1.70; P-value 5 0.0006] and the other was an intronic SNP in high linkage disequilibrium with rs2888805 (rs4135150). None of the associations had a P-value <6.6310(-5), the threshold for statistical significance after correcting for multiple comparisons. The results pinpoint DNA repair genes most likely to contribute to the NMSC cancer-prone phenotype. A promising lead is genetic variants in TDG, important not only in base excision repair but also in regulating the epigenome and gene expression, which may contribute to the NMSC-associated increase in overall cancer risk.

An engineering intervention resulting in improvement in lung function and change in urinary 8-hydroxydeoxyguanosine among foundry workers in Taiwan.

PURPOSE: To assess changes in oxidative DNA damage and lung function amongst a group of foundry workers resulting from an engineering intervention to reduce air respirable dust in their working environment. METHODS: We studied all 22 workers recruited from a typical small Taiwanese iron foundry plant before and 3 months after improvements to air exhaust control. The effectiveness of the air exhaust intervention in reducing respirable dust and SiO2 was determined by personal breathing-zone air sampling. Initial baseline biomarker measurements were taken of lung function and urinary 8-hydroxy-deoxyguanosine (8-OHdG) in all of the workers, with follow-up measurements taken 3 months after the engineering control was put in place. Generalized estimating equations were used to assess the effect of the intervention on lung function and oxidative DNA damage. RESULTS: Following the intervention, respirable dust density decreased from 2.87 ± 1.38 mg/m³ to 1.60 ± 0.70 mg/m³ (p = 0.07), and SiO2 concentration decreased from 0.43 ± 0.25 mg/m³ to 0.18 ± 0.11 mg/m³ (p < 0.05). Compared to initial baseline, significant improvements were found in lung function (FVC, FEV1, FVC%pred and FEV1%pred) amongst the workers after the engineering intervention. A significant increase in concentration of urinary 8-OHdG was observed after the engineering intervention in smokers, but not in non-smokers. CONCLUSIONS: These findings indicate that reductions in workplace respirable dust and SiO2 concentration can result in improved lung function amongst foundry workers.

EXPOSURE ASSESSMENT OF RAYONG OIL SPILL CLEANUP WORKERS.

Background: In July of 2013, a pipeline connecting an offshore oil platform to a tanker caused crude oil to spill into the Sea of Rayong off the coast of Thailand. The resulting oil slick, estimated to be between 50 and 190 cubic meters (336-1,200 barrels), washed ashore one day later on the island of Samet. We conducted a study to quantify internal dose of polycyclic aromatic hydrocarbons (PAHs) and benzene in 1,262 oil spill cleanup workers, and to examine factors related to their dose. Methods: Frozen stored urine samples (n=1343) collected from the workers during the one month cleanup period were used to measure the concentration of 1-hydroxypyrene-glucuronide (1-OHPG), cotinine and creatinine. Data from questionnaires and urinary trans,trans-muconic acid (t,t-MA), a benzene metabolite, measured previously as part of a worker health surveillance plan, were linked with the laboratory data. Results: The internal dose of urinary 1-OHPG was highest in individuals who worked during the first 3 days of cleanup work (median: 0.97 pmol/ml) and was 66.7% lower (median: 0.32 pmol/ml) among individuals who worked in the final week of the study (days 21-28). After adjusting for age, cotinineand creatinine by regression analysis, the decline in urinary 1-OHPG concentration with days of cleanup remained significant (P-trend <0.001). A decreasing trend by days of cleanup was also observed for detectable urinary t,t-MA percentage (P-trend <0.001). Conclusion: Rayong oil spill cleanup workers exhibited evidence of elevated levels of PAH and benzene exposure during the early weeks of cleanup, compared to near background levels 4 weeks after cleanup began. Long-term health monitoring of oil spill cleanup workers is advised.

Involuntary tobacco smoke exposure and urinary levels of polycyclic aromatic hydrocarbons in the United States, 1999 to 2002.

Evidence supports active smoking as a major source of exposure to polycyclic aromatic hydrocarbons (PAH), compounds that are mutagenic and carcinogenic in humans. The influence of involuntary exposure to tobacco smoke on PAH exposure levels among nonsmokers, however, is unknown. This study evaluated the association between both active and involuntary tobacco smoke and biomarkers of PAH exposure in the general U.S. population. A cross-sectional analysis of 5,060 participants>or=6 years of age was done using data from the 1999-2002 National Health and Nutrition Examination Survey (NHANES). PAH exposure was measured by urinary concentrations of 23 monohydroxylated metabolites of nine PAH compounds. Tobacco smoke exposure was defined as no exposure, involuntary exposure, and active exposure by combining serum cotinine levels, smoking status, and presence of household smokers. PAH metabolite levels ranged from 33.9 ng/L for 9-hydroxyphenanthrene to 2,465.4 ng/L for 2-hydroxynaphthalene. After adjustment for age, sex, race/ethnicity, education, household income, and broiled/grilled food consumption, participants involuntarily and actively exposed to tobacco smoke had urinary metabolite concentrations that were increased by a factor of 1.1 to 1.4 and 1.5 to 6.9, respectively, compared with unexposed participants. Associations for involuntary smoking were stronger and statistically significant for 1-hydroxypyrene, 2-hydroxyfluorene, 3-hydroxyfluorene, 9-hydroxyfluorene, 1-hydroxyphenanthrene, 2-hydroxyphenanthrene, and 3-hydroxyphenanthrene compared with other metabolites. Involuntary exposure to tobacco smoke was associated with elevated urinary concentrations of most PAH metabolites in a representative sample of the U.S. population. Policy and educational efforts must continue to minimize PAH exposure through active and involuntary tobacco smoke exposure.

Determinants of urinary 1-hydroxypyrene glucuronide in South Korean children.

OBJECTIVES: This study was conducted to investigate the dominant sources of the urinary pyrene metabolite, 1-hydroxypyrene glucuronide (1-OHPG), in South Korean children. METHODS: Urine samples were collected from 102 non-smoking children (aged 10-14). Urinary 1-OHPG was assayed by synchronous fluorescence spectroscopy, following immuno-affinity purification using monoclonal antibody 8E11. Urinary cotinine, a metabolite of nicotine, was measured by GC/MS. Information on environmental tobacco smoke (ETS) exposure, diet, fuel type for heating home, and other possible sources of PAH exposure was collected by self-administered questionnaires. RESULTS: Mean (+/-SE) 1-OHPG levels were 1.64 (+/-0.06) ng/ml (range 0.04-3.27 ng/ml). Two multiple linear regression analyses (differing in how ETS was approximated: by parental smoking or urinary cotinine) revealed a positive association between urinary 1-OHPG levels and parental smoking at home (P = 0.007), log urinary cotinine (P = 0.165), frequent grilled (shell)fish consumption (P = 0.061), and living in a commercial/other zone (P = 0.007) versus a residential or industrial zone. No consistent associations were found between 1-OHPG and the child's sex, grilled meat consumption, or fuels used to heat the home. CONCLUSIONS: These results support that ETS, frequent grilled fish consumption, and the ambient environment are important predictors of urinary 1-OHPG levels in South Korean children.

Polychlorinated biphenyl levels in peripheral blood and non-Hodgkin's lymphoma: a report from three cohorts.

The incidence of non-Hodgkin's lymphoma (NHL) unrelated to HIV infection has steadily increased over the past several decades and remains substantially unexplained. Limited evidence suggests that increased concentrations of polychlorinated biphenyls (PCB) measured in blood or fat tissue are associated with increased risk of NHL. Although PCB congeners vary in their biological activity, the relation between individual congeners and NHL risk has not been examined previously using prospectively collected biospecimens. We examined congener-specific associations in three prospective cohorts. Prediagnostic serum or plasma concentrations of selected PCB congeners were measured among NHL cases and controls from these cohorts: Janus (190 cases and 190 controls) in Norway and CLUE I (74 cases and 147 controls) and the Nurses' Health Study (30 cases and 78 controls) in the United States. All blood samples were collected in the 1970s or 1980s. We used logistic regression to calculate odds ratios (OR) and 95% confidence intervals (95% CI) for the relations between risk of NHL and lipid-corrected plasma or serum concentrations. Several congeners (i.e., 118, 138, and 153) that were present at higher levels and were moderately to highly correlated with each other showed exposure-response trends with risk of NHL in all three cohorts. These associations were observed primarily among subjects diagnosed closer to the date of blood collection in the two cohorts with sufficient cases to permit stratification by time. Among cases diagnosed within the median years of follow-up (16 years in Janus and 12 years in CLUE I), ORs and 95% CIs for increasing fourths of concentration of congener 118 relative to the lowest fourth were as follows: 2.4 (0.9-6.5), 4.9 (1.6-15.3), and 5.3 (1.5-18.8; P(trend) < 0.005) in Janus and 8.1 (1.0-68.9), 6.6 (0.7-59.0), and 13.0 (1.6-106.8; P(trend) < 0.05) in CLUE I. Similar patterns were seen for congeners 138 and 153 and for total PCBs. Limited evidence of exposure-response trends was also observed for several other congeners. The primary 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane metabolite, p,p'-DDE, was not significantly associated with NHL in most analyses but slightly to moderately confounded the PCB associations. The results from these three cohorts suggest that concentrations of certain PCBs in blood are associated with increased risk of NHL.

Predictors of polycyclic aromatic hydrocarbon exposure and internal dose in inner city Baltimore children.

Polycyclic aromatic hydrocarbons (PAHs), the by-products of incomplete combustion of organic materials, are commonly found on particulate matter (PM) and have been associated with the development of asthma and asthma exacerbation in urban populations. We examined time spent in the home and outdoors as predictors of exposures to airborne PAHs and measured urinary 1-hydroxypyrene-glucuronide (1-OHPG) as internal dose of PAHs in 118 children aged 5-12 years from Baltimore, MD. During weeklong periods (Saturday-Saturday) in each of four seasons: daily activities were assessed using questionnaires, indoor air nicotine and PM concentrations were monitored, and urine specimens were collected on Tuesday (day 3) and Saturday (day 7) for measurement of 1-OHPG. Time spent in non-smoking homes was associated with significantly decreased 1-OHPG concentration in urine (ß=-0.045, 95% CI (-0.076, -0.013)), and secondhand smoke (SHS) exposures modified these associations, with higher urinary 1-OHPG concentrations in children spending time in smoking homes than non-smoking homes (P-value for interaction=0.012). Time spent outdoors was associated with increased urinary 1-OHPG concentrations (ß=0.097, 95% CI (0.037, 0.157)) in boys only. Our results suggest that SHS and ambient (outdoor) air pollution contribute to internal dose of PAHs in inner city children.

Higher urine 1-hydroxy pyrene glucuronide (1-OHPG) is associated with tobacco smoke exposure and drinking maté in healthy subjects from Rio Grande do Sul, Brazil.

BACKGROUND: The highest rates of esophageal squamous cell carcinoma (ESCC) in Brazil occur in Rio Grande do Sul, the most southern state, which has incidence rates of 20.4/100,000/year for men and 6.5/100,000/year for women. Exposure to carcinogenic polycyclic aromatic hydrocarbons (PAHs) through tobacco smoke and other sources may increase the risk of ESCC. The aims of the current study were to investigate the degree and sources of PAH exposure of the inhabitants of this region of southern Brazil. METHODS: Two hundred healthy adults (half smokers, half non smokers, half male and half female) were recruited, given a standardized questionnaire, and asked to provide a urine sample for measurement of 1-hydroxypyrene glucuronide (1-OHPG), a PAH metabolite). Urine 1-OHPG concentrations were measured using immunoaffinity chromatography and synchronous fluorescence spectroscopy and urine cotinine was measured using a dipstick test. We examined factors associated with 1-OHPG concentration using Wilcoxon tests and multiple linear regression. RESULTS: Urine 1-hydroxypyrene glucuronide (1-OHPG) was successfully measured on 199 subjects. The median (interquartile range) of urine 1-OHPG in the 199 participants was 2.09 pmol/mL (0.51, 5.84). Tobacco smoke exposure and maté drinking were statistically significantly associated with higher urine 1-OHPG concentrations in the multivariate linear regression model. CONCLUSION: Tobacco smoke and maté both contribute to high levels of benzo[a]pyrene exposure in the people of southern Brazil. This high PAH exposure may contribute to the high rates of ESCC observed in this population. The increased urine 1-OHPG concentrations associated with maté suggest that contaminants, not just thermal injury, may help explain the increased risk of ESCC previously reported for maté consumption.

Influence of geographic location in modeling blood pesticide levels in a community surrounding a U.S. Environmental protection agency superfund site.

In this study we evaluated residential location as a potential determinant for exposure to organochlorine compounds. We investigated the geographic distribution characteristics of organochlorine levels in approximately 1,374 blood samples collected in 1974 from residents of a community with a potential organochlorine source. Street addresses of Washington County, Maryland, residents were obtained and geocoded in a geographic information system. We used multivariate linear regression models to characterize the blood organochlorine levels of these residents that had been analyzed as part of previous studies using both environmental- and individual-level covariates. This was done to evaluate if the geographic distribution of blood levels in participants was related to the environmental source in the community. Model inference was based on generalized least squares to account for residual spatial variation. A significant inverse relationship was found between blood dieldrin levels and residential distance from the potential source. For every mile of distance from the source, blood dieldrin levels decreased 1.6 ng/g in study participants (p-value = 0.042), adjusting for age, sex, education level, smoking status, and drinking water source. 1,1-Dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) levels in the blood did not change significantly based on residential distance from the source, taking the same covariates into account. However, these results are limited by the inability to account for several potential confounders. This study demonstrates that spatially distributed covariates may play an important role in individual exposure patterns. Spatial information may enable researchers to detect a potential exposure pattern that may not be revealed with only nonspatial variables.

High exposure to polycyclic aromatic hydrocarbons may contribute to high risk of esophageal cancer in northeastern Iran.

BACKGROUND: The northeastern region of Iran has some of the highest rates of esophageal squamous cell carcinoma (ESCC) in the world. MATERIALS AND METHODS: To investigate the role of polycyclic aromatic hydrocarbons (PAHs) in the etiology of ESCC in northeastern Iran, we measured urine 1-hydroxypyrene glucuronide (1-OHPG), a stable PAH metabolite, in 99 inhabitants of this area. RESULTS: The median urine 1-OHPG in participants of this study was 4.2 pmol/ml. Forty-two subjects (42%) had levels ranging from 1 to 5 pmol/ml, indicative of moderate PAH exposure, and 41 (41%) had levels above 5 pmol/ml, indicative of very high exposure. Further analysis showed that 1-OHPG levels were high in all subgroups of our study subjects, including both sexes, rural and urban dwellers, and smokers and non-smokers. Only 15% of the variance in 1-OHPG was explained by age, sex, residence, smoking, nass, or opium consumption. This pattern of PAH exposure parallels the ESCC incidence pattern seen in this area. CONCLUSION: We conclude that people in northeastern Iran are exposed to widespread and very high levels of PAH, largely from unknown sources, and this may contribute to the high rates of ESCC observed in this area.

Design issues in cross-sectional biomarkers studies: urinary biomarkers of PAH exposure and oxidative stress.

Cross-sectional biomarker studies can provide a snapshot of the frequency and characteristics of exposure/disease in a population at a particular point in time and, as a result, valuable insights for delineating the multi-step association between exposure and disease occurrence. Three major issues should be considered when designing biomarker studies: selection of appropriate biomarkers, the assay (laboratory validity), and the population validity of the selected biomarkers. Factors related to biomarker selection include biological relevance, specificity, sensitivity, biological half-life, stability, and so on. The assay attributes include limit of detection, reproducibility/reliability, inter-laboratory variation, specificity, time, and cost. Factors related to the population validity include the frequency or prevalence of markers, greater inter-individual variation than intra-individual variation, intra-class correlation coefficients (ICC), association with potential confounders, invasiveness of specimen collection, and subject selection. Three studies are selected to demonstrate different features of cross-sectional biomarker studies: (1) characterizing the determinants of the biomarkers (study I: urinary PAH metabolites and environmental particulate exposure), (2) relationship of multiple biomarkers of exposure and effect (study II: relationship between urinary PAH metabolites and oxidative stress), and (3) evaluating gene-environmental interaction (study III: effect of genetic polymorphisms of GSTM1 on the association of green tea consumption and urinary 1-OHPG levels in shipbuilding workers).

The effect of clinical UVA/B exposures on urinary urocanic acid isomer levels in individuals with caucasian type (II/III) skin types.

Terrestrial ultraviolet radiation (UVR) exposure, consisting of ultraviolet A (320-40 nm) and B (290-320 nm), results in the photoisomerizion of epidermal trans-urocanic acid (trans-UCA) to cis-urocanic acid (cis-UCA), a potential suppressor of local and systemic immune responses. This study examines urinary UCA isomers as biomarkers of UVA/B exposure. It presents results measuring both cis- and trans-UCA in human urine samples collected from a group of study subjects (skin types II/III) that underwent controlled UVA/B exposures similar to those administered in commercial suntanning parlors. The UCA isomers were purified from urine using C18 solid-phase extraction columns followed by high-performance liquid chromatography (HPLC) with UV absorbance (268 nm) detection. The UCA biomarker was expressed as the ratio of cis-UCA to trans-UCA (UCA ratio), or as cis-UCA concentration corrected for urine volume using creatinine (cis-UCA-Cr). The UCA ratio increased over baseline in the urine of individuals exposed to UVA/B. A single exposure to approximately 70 percent minimal erythema dose (MED) of UVR (95 % UVA/5 % UVB to approximately 90 % of skin area) produced a 4.75-fold increase in the UCA ratio (p< 0.001) relative to baseline. Repeated daily UV exposures of similar doses produced a minimal increase in UCA ratio above that of the single UV exposure. These findings indicate that UCA cis-trans ratio holds promise as a biomarker for recent solar UV exposure.

XPD polymorphism and risk of subsequent cancer in individuals with nonmelanoma skin cancer.

BACKGROUND: Individuals with nonmelanoma skin cancer (NMSC) are at increased risk of developing subsequent cancers. Genetic predisposition to reduced DNA repair capacity may be an underlying susceptibility factor explaining the excess risk of malignancies. To test this hypothesis, a cohort study was conducted to examine the association between XPD Lys751Gln polymorphism and risk of a second primary cancer in individuals with NMSC. METHODS: A subgroup of 481 individuals with a history of NMSC who participated in the CLUE II community-based cohort was followed for the development of a second primary cancer. Blood specimens donated in 1989 were genotyped for the XPD Lys751Gln polymorphism using the 5' nuclease assay. Cox proportional regression with delayed entry was used to calculate the incidence rate ratio (IRR) and 95% confidence interval (95% CI) for risk of developing a second primary cancer according to XPD genotype. All statistical tests were two sided. RESULTS: Eighty individuals developed a second primary cancer. The most frequent occurring cancers were of the prostate (18%), lung (15%), and breast (15%). Persons with at least one Gln allele had an increased risk of a second primary cancer compared with the reference Lys/Lys genotype (adjusted IRR 2.22, 95% CI 1.30-3.76). When the reference category was limited to never smokers with the Lys/Lys genotype, the risk of developing a second primary cancer associated with having at least one Gln allele was increased >3-fold in both never smokers (IRR 3.93, 95% CI 1.36-11.36) and ever smokers (IRR 6.14, 95% CI 2.17-17.37). CONCLUSION: These findings suggest that individuals with NMSC who have the variant XPD Gln allele are at increased risk of developing a second primary cancer.

Risk of non-Hodgkin's lymphoma and prediagnostic serum organochlorines: beta-hexachlorocyclohexane, chlordane/heptachlor-related compounds, dieldrin, and hexachlorobenzene.

Increases in non-Hodgkin's lymphoma (NHL) incidence and mortality rates during the past few decades remain largely unexplained. Studies suggest that organochlorine pesticides may contribute to an increased risk of NHL. In 1974, serum samples were obtained from 25,802 participants in the Campaign Against Cancer and Stroke in Washington County, Maryland (USA), and cryopreserved for future study. We measured prediagnostic levels of chlordane, lindane (gamma-hexachlorocyclohexane), beta-hexachlorocyclohexane, transnonachlor, heptachlor, heptachlor epoxide, oxychlordane, dieldrin, and hexachlorobenzene in serum samples of 74 cases of NHL and 147 matched controls. Previously, we found an association between NHL and serum levels of total PCBs (polychlorinated biphenyls), but not DDT (dichlorodiphenyltrichloroethane) and related compounds. In this instance, there was no evidence of an association between NHL risk and serum levels of any of the individual lipid- and recovery-corrected organochlorines that we evaluated, nor of the summed chlordane-related compounds (transnonachlor, heptachlor, heptachlor epoxide, oxychlordane). These findings do not support the hypothesis that the organochlorine compounds included in this study are strongly linked to the development of NHL. The possibility of a weak association cannot be excluded by these data.

Metabolites of 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) in human urine after consumption of charbroiled or fried beef.

Heterocyclic amines (HAs) are carcinogenic combustion products formed during the cooking of meat at moderate to high temperatures. PhIP is the most common HA formed in fried, grilled or broiled meat, and is a colon, breast, and prostate carcinogen in rodents. The major metabolites of PhIP detected in human urine are N(2)-OH-PhIP-N(2)-glucuronide, PhIP-N(2)-glucuronide, N(2)-OH-PhIP-N(3)-glucuronide, and 4'-PhIP-sulphate. We have measured the time course of PhIP in untreated and acid- or alkali-hydrolyzed urines from 10 healthy non-smoking subjects ingesting identical amounts of char-broiled beef (containing both HAs and PAHs) for 5 days. The morning after the first day of broiled beef consumption (containing 7.7 micro g PhIP), urinary concentration of PhIP increased 14- to 38-fold above mean prefeed concentration. Following cessation of broiled meat consumption, urinary PhIP declined to near prefeed levels within 48-72 h. The ratio of alkali-labile PhIP metabolites to unmetabolized PhIP varied by 2.7-fold among subjects, ranging from 18:1 to 48:1. In a subsequent study we measured PhIP in acid-hydrolyzed urine from 66 subjects ingesting beef pan-fried at high temperature. A significant correlation (r=0.61, P<0.0001) was observed between the amount of fried meat ingested and concentration of PhIP in urines collected between 0 and 12h after feeding. Other investigators have identified 2-OH-PhIP in acid-hydrolyzed urine from these subjects, and also observed a significant correlation (r=0.52, P<0.0001) with the amount of fried meat ingested. Additional studies have measured PhIP metabolites in subjects consuming their normal (unrestricted) diet. PhIP was detected in acid-hydrolyzed urine from 20 to 50% of these subjects, depending on ethnic group. Taken together, these studies indicate that significant amounts of PhIP are bioavailable from ingestion of fried or char-broiled meats, and that urinary PhIP metabolites reflect recent (12-24h) ingestion. Furthermore, significant interindividual differences in the amounts of urinary PhIP metabolite excreted are observed following ingestion of similar amounts of PhIP. These differences do not correlate with interindividual differences in excretion of urinary pyrene metabolites in the same individuals after ingestion of char-broiled beef, indicating that levels of PhIP and pyrene metabolites in human urine are mediated by compound-specific metabolic factors.