Feasibility and acceptance of cervicovaginal self-sampling within the German National Cohort (Pretest 2).

BACKGROUND AND OBJECTIVES: Within the German National Cohort (GNC) 100,000 adult women in Germany will be comprehensively interviewed and examined. While women's health is addressed in the basic interview, direct detection of cervicovaginal microbial colonisation or infection is not part of the examination protocol. In a pilot project the feasibility of female study participants of the GNC collecting a cervicovaginal lavage at home without having to involve a gynecologist or other medical personnel was thus investigated. The ability of the procedure to detect vaginal microbes and conditions including human papillomavirus (HPV), Chlamydia trachomatis and bacterial vaginosis (BV) were also explored. METHODS: This cross-sectional study was conducted in two study centers (Hamburg and Hanover) of the GNC during Pretest 2 in 2012 as an add-on module to the main program of the National Cohort. Participants were randomly selected through the population registration office. After providing written informed consent at the study center, participants self-collected a cervicovaginal lavage (Delphi Screener™) at home following written instructions. Participants mailed samples and acceptability questionnaires to the laboratory and the study center, respectively. Acceptability of self-sampling was categorized as consent, partial consent and rejection. The samples were analyzed by multiplex HPV genotyping for the presence of 27 mucosal HPV subtypes. To detect other pathogens "Sexually Transmitted Infection Profiling" (STIP) was used, a novel multiplex polymerase chain reaction (PCR) for various vaginally occurring pathogens/conditions coupled with subsequent bead-based Luminex(®) hybridization. Human beta-globin and DNA polymerase alpha (PolA) sequences were used as positive controls for the detection of human DNA during HPV detection and STIP, respectively. RESULTS: The participation based on the proportion of all women in Pretest 2 who could take part in the add-on Pretest 2 was 67.3 % (109 out of 162). The age of participants ranged from 20 to 69 years. The self-reported median duration of the collection of the lavage was 5 min. Analysis of the questionnaires (n = 108) revealed that the self-sampling of a cervicovaginal lavage was acceptable to 98 % of women (106 out of 108), and considered to be easy by 89 % (96 out of 108) as well as user-friendly by 96 % of the women (104 out of 108). Human beta-globin and PolA as markers for human DNA and sample quality were detected in all samples analyzed while HPV as a marker for pathogen detectability was identified in 18 out of 109 samples. Of the 107 samples tested with STIP as a second marker for pathogen detectability, 5 samples were excluded from statistical analyses on bacterial colonization because of signs in the laboratory results of the use of antibiotics. For the computation of the possible occurrence of bacterial vaginosis and candidiasis 7 and 8 samples, respectively, were excluded because of low signal intensities resulting in an evaluation of 95 or 94 samples, respectively. Ureaplasma parvum was detected in 22 out of 102 samples, BV in 14 out of 95 samples and candidiasis in 13 out of 94 samples. Chlamydia trachomatis was not detected in any sample. CONCLUSION: The feasibility study on cervicovaginal self-sampling indicates that this form of biosampling was very well accepted within the framework of the GNC and feasible in terms of pathogen detection. Its further application in the GNC would allow investigation of transience and persistence, or long-term effects of vaginal (co)infections and colonization.

Collection of vaccination data in the German National Cohort : Findings of a feasibility study in three study centers.

BACKGROUND: Data about the vaccination status of participants are required in epidemiological cohort studies whenever infection or immunity is considered as potential exposure or outcome. Within Pretest 2 of the German National Cohort (GNC) we therefore investigated the acceptance and feasibility of extracting vaccination status from vaccination certificates provided by the participants of the study. METHODS: This study was conducted in three study centers (Bremen, n = 73; Hamburg, n = 200; Hannover, n = 193). In order to test if an additional reminder would prevent participants from forgetting their vaccination certificates at home persons willing to participate in Pretest 2 were randomly assigned to one of three invitation groups (IG). About one third of the participants received either no further reminder (IG1), a reminder card together with the appointment letter (IG2) or a separate reminder card 4 days before the appointment (IG3). At the study center, vaccination data were scanned or copied and entered into a database using a unique identification number. Participants were also asked to fill in a short questionnaire to assess the completeness of the provided vaccination data. Additionally, in one of the three participating study centers, general practitioners (GP) were asked to provide vaccination data from their records following respective participants' consent. Finally, we compared the influenza data from the vaccination certificates with the influenza data obtained from participants in Pretest 2 by use of a self-administered questionnaire (ID-Screen). RESULTS: Due to different starting dates of the study the intended reminder procedure was implemented only in Hamburg and Hannover. In Hamburg, significantly more vaccination certificates were submitted by the group which received the reminder card separately 4 days before the examination (IG3) compared to IG1 and IG2 (p = 0.04). In Hannover, in contrast, most vaccination certificates were brought by those who received the reminder card together with the appointment letter. Overall, the use of a reminder card had a positive but not significant effect as 89 % (185/209) of participants who received the reminder card submitted vaccination data versus 81 % (84/104) of participants who did not receive any reminder card (p = 0.06). Of all Pretest 2 participants in Hannover, 62 % (120/193) gave written consent for data collection by the GPs. In total, 114 practices were contacted of which 49 (43 %) sent vaccination data. All in all, 360 vaccination certificates with 5065 documented vaccinations were entered into a database, of which 4830 (95 %) were valid for analysis covering a period from 1946 to 2012. The comparison of influenza vaccination data from vaccination certificates to the remembered data from a self-completed questionnaire showed an agreement of data in 46 % (84/184) of cases (Kappa = 0.48). Influenza vaccinations were underreported in 4 % (7/170) of self-completed questionnaires. CONCLUSION: The reliable documentation of vaccinations within the context of the GNC proved to be feasible and thus recommendable at a large scale within the GNC as participants showed high willingness and compliance in providing available vaccination documents. An additional validation by means of documents provided by physicians seems to be possible for more than a quarter of participants. In order to maximize the likelyhood of participants' of bringing their vaccination certificates it would be sufficient to send a reminder card together with the appointment letter.

Dietary patterns and survival in German postmenopausal breast cancer survivors.

BACKGROUND: Research on the association between dietary patterns and breast cancer survival is very limited. METHODS: A prospective follow-up study was conducted in Germany, including 2522 postmenopausal breast cancer patients diagnosed in 2001-2005 with available food frequency questionnaire data. Vital status, causes of death, and recurrences were verified through the end of 2009. Principle component factor analysis was used to identify pre-diagnostic dietary patterns. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated with Cox proportional hazards models. RESULTS: Two major dietary patterns were identified: 'healthy' (high intakes of vegetables, fruits, vegetable oil, sauces/condiments, and soups/bouillons) and 'unhealthy' (high intakes of red meat, processed meat, and deep-frying fat). Increasing consumption of an 'unhealthy' dietary pattern was associated with an increased risk of non-breast cancer mortality (highest vs lowest quartile: HR, 3.69; 95% CI, 1.66-8.17; P-trend <0.001). No associations with breast cancer-specific mortality and breast cancer recurrence were found. The 'healthy' dietary pattern was inversely associated with overall mortality (HR, 0.74; 95% CI, 0.47-1.15; P-trend=0.02) and breast cancer recurrence (HR, 0.71; 95% CI, 0.48-1.06; P-trend=0.02) in stage I-IIIa patients only. CONCLUSION: Increasing intake of an 'unhealthy' pre-diagnostic dietary pattern may increase the risk of non-breast cancer mortality, whereas increasing intake of a 'healthy' pattern may reduce the risk of overall mortality and breast cancer recurrence.

Polymorphism Thr160Thr in SRD5A1, involved in the progesterone metabolism, modifies postmenopausal breast cancer risk associated with menopausal hormone therapy.

Menopausal hormone therapy (MHT) is associated with an increased breast cancer risk in postmenopausal women, with combined estrogen-progestagen therapy posing a greater risk than estrogen monotherapy. However, few studies focused on potential effect modification of MHT-associated breast cancer risk by genetic polymorphisms in the progesterone metabolism. We assessed effect modification of MHT use by five coding single nucleotide polymorphisms (SNPs) in the progesterone metabolizing enzymes AKR1C3 (rs7741), AKR1C4 (rs3829125, rs17134592), and SRD5A1 (rs248793, rs3736316) using a two-center population-based case-control study from Germany with 2,502 postmenopausal breast cancer patients and 4,833 matched controls. An empirical-Bayes procedure that tests for interaction using a weighted combination of the prospective and the retrospective case-control estimators as well as standard prospective logistic regression were applied to assess multiplicative statistical interaction between polymorphisms and duration of MHT use with regard to breast cancer risk assuming a log-additive mode of inheritance. No genetic marginal effects were observed. Breast cancer risk associated with duration of combined therapy was significantly modified by SRD5A1_rs3736316, showing a reduced risk elevation in carriers of the minor allele (p (interaction,empirical-Bayes) = 0.006 using the empirical-Bayes method, p (interaction,logistic regression) = 0.013 using logistic regression). The risk associated with duration of use of monotherapy was increased by AKR1C3_rs7741 in minor allele carriers (p (interaction,empirical-Bayes) = 0.083, p (interaction,logistic regression) = 0.029) and decreased in minor allele carriers of two SNPs in AKR1C4 (rs3829125: p (interaction,empirical-Bayes) = 0.07, p (interaction,logistic regression) = 0.021; rs17134592: p (interaction,empirical-Bayes) = 0.101, p (interaction,logistic regression) = 0.038). After Bonferroni correction for multiple testing only SRD5A1_rs3736316 assessed using the empirical-Bayes method remained significant. Postmenopausal breast cancer risk associated with combined therapy may be modified by genetic variation in SRD5A1. Further well-powered studies are, however, required to replicate our finding.

Estimated enterolignans, lignan-rich foods, and fibre in relation to survival after postmenopausal breast cancer.

BACKGROUND: Lignans - oestrogenic substances present in various foods - are associated with postmenopausal breast cancer risk, but not much is known regarding their effects on survival. METHODS: In a follow-up study of 2653 postmenopausal breast cancer patients diagnosed between 2001 and 2005, vital status and causes of death were verified through end of 2009. Hazard ratios (HRs) and 95% confidence intervals (CIs) for estimated enterolignans, lignan-rich foods, and dietary fibre in relation to overall survival (OS) and breast cancer-specific survival (BCSS) were assessed using Cox proportional hazards models stratified by age at diagnosis and adjusted for prognostic/confounding factors. RESULTS: Median follow-up time was 6.4 years, and 321 women died, 235 with breast cancer. High estimated enterolactone and enterodiol levels were associated with significantly lower overall mortality (highest quintile, HR=0.60, 95% CI=0.40-0.89, P(Trend)=0.02 and HR=0.63, 95% CI=0.42-0.95, P(Trend)=0.02, respectively). Fibre intake was also associated with a significantly lower overall mortality. Differentiated by median fibre intake, associations with estimated enterolignans were still evident at low but not high fibre intake. There was no effect modification by oestrogen receptor status and menopausal hormone therapy. CONCLUSION: Postmenopausal breast cancer patients with high estimated enterolignans may have a better survival.

The impact of menopausal hormone therapy on the incidence of different breast cancer types--data from the Cancer Registry Hamburg 1991-2006.

BACKGROUND: The publication of the Women's Health Initiative Study [1] in 2002 and the Million Women Study [31] in 2003 on the association of menopausal hormone therapy (HT) and breast cancer were followed by a decrease in the prescription of HT to menopausal women in western countries. In the following years several papers from different countries reported declines in breast cancer incidence and discuss whether this decline is related to the decreased use of menopausal hormone therapy. METHODS: We contribute further data by analysing breast cancer incidence rates from the Hamburg Cancer Registry, Germany, for the time period 1991-2006 and HT use data from a large case-control study conducted in the Hamburg region. At first we determined whether there is a decline in breast cancer incidence in 2002/2003. To find supporting evidence for a causal relationship between breast cancer incidence and use of menopausal hormones we addressed the following issues: The decline in incidence should be more pronounced in the age groups, in which HT is used predominantly, i.e. age group 50-69. The decline in incidence should be most pronounced for breast cancer types more strongly associated with HT, i.e. invasive lobular cancer. RESULTS: We observed a statistical significant decline in incidence of all invasive breast cancer in 2002/2003 in Hamburg. The increase in breast cancer incidence as well as the decline was most pronounced in the age group 50-69. Regarding the histological types of tumours in this age group the decline was only pronounced for invasive lobular cancer. The estimated prevalence of HT indicates a decreasing hormone use starting in 2001/2002. We found a strong decrease in prescriptions for menopausal hormone therapy between 2002 and 2005. CONCLUSION: In summary, our data add to the evidence of a relation between breast cancer incidence and menopausal hormone use.

Physical activity and postmenopausal breast cancer: effect modification by other breast cancer risk factors.

OBJECTIVES: Epidemiological evidence suggests an inverse association between physical activity (PA) and postmenopausal breast cancer risk. Breast cancer is a heterogeneous disease, influenced by reproductive factors, lifestyle pattern, and predispositions. We investigated whether these risk factors modify the effect of PA on breast cancer risk. METHODS: We analyzed data from 2004 hormone-receptor-positive postmenopausal breast cancer cases and 6569 controls from the population-based MARIE study conducted 2002-2005 in Germany. Interaction was statistically tested using adjusted unconditional logistic regression models. RESULTS: The inverse association between leisure-time PA and risk of postmenopausal hormone-receptor-positive breast cancer was not heterogeneous by family history of breast cancer or by hormone therapy. PA showed a significant interaction with benign breast diseases (p = 0.023) and with breastfeeding (p = 0.045) but not with parity (p = 0.94), with clear risk reductions only for women who ever had breastfed or who ever had a benign breast disease (among ever breastfed: odds ratio = 0.63; 95% confidence interval = (0.52, 0.77), highest vs. lowest PA quartile). Interaction with BMI was weak (p = 0.053). CONCLUSIONS: Breastfeeding and benign breast diseases modified the effect of PA on postmenopausal breast cancer risk. If other studies find similar modifications, increasing knowledge about these risk factors may contribute to a better understanding of the mode of action of PA on breast cancer risk. For women who are at higher risk for breast cancer due to family history or due to hormone therapy use, it is encouraging that they might lower their risk by being physically active.

Good agreement between physician and self-reported hormone therapy data in a case-control study.

OBJECTIVE: In a population-based case-control study examining the effects of postmenopausal hormone therapy (HT) on breast cancer risk, the authors conducted a validation study comparing prescription data from gynecologists with self-reports. STUDY DESIGN AND SETTING: The study was conducted in the Rhein-Neckar and Hamburg regions of Germany from 2002 to 2005. A total of 224 cases and 225 controls, stratified by region, age, and hormone use were randomly selected for the validation study. RESULTS: For ever/never use 88.2% agreement was seen, and agreement for ever/never use by type of HT was 80.6%, 80.3%, and 90.5% for mono-estrogen, cyclical combined, and continuous combined therapy, respectively. The intraclass correlation coefficient (ICC) for duration of use was high, 0.82 (95% confidence interval [CI]: 0.77, 0.85), as were the ICCs for age at first and last use, 0.88 (95% CI: 0.85, 0.91) and 0.98 (95% CI: 0.97, 0.98). Despite the exceptionally high number of different HT prescriptions available in Germany, comparison of exact brand name resulted in perfect agreement for 50.2% of participants, partial agreement for 29.3%, and no agreement for 20.7%. In general, agreement was not differential by disease status. CONCLUSION: Overall, the self-reported HT of the study participants corresponded well with physicians' reports.

Estimation of dioxin and furan elimination rates with a pharmacokinetic model.

Quantitative description of the pharmacokinetics of dioxins and furans in humans can be of great help for the assessment of health risks posed by these compounds. To that the elimination rates of sixteen 2,3,7,8-chlorinated dibenzodioxins and dibenzofurans are estimated from both a longitudinal and a cross-sectional data set using the model of Van der Molen et al. [Van der Molen G.W., Kooijman S.A.L.M., and Slob W. A generic toxicokinetic model for persistent lipophilic compounds in humans: an application to TCDD. Fundam Appl Toxicol 1996: 31: 83-94]. In this model the elimination rate is given by the (constant) specific elimination rate multiplied with the ratio between the lipid weight of the liver and total body lipid weight. Body composition, body weight and intake are assumed to depend on age. The elimination rate is, therefore, not constant. For 49-year-old males, the elimination rate estimates range between 0.03 per year for 1,2,3,6,7,8-hexaCDF to 1.0 per year for octaCDF. The elimination rates of the most toxic congeners, 2,3,7,8-tetraCDD, 1,2,3,7,8-pentaCDD, and 2,3,4,7,8-pentaCDF, were estimated at 0.09, 0.06, and 0.07, respectively, based on the cross-sectional data, and 0.11, 0.09, and 0.09 based on the longitudinal data. The elimination rates of dioxins decrease with age between 0.0011 per year for 1,2,3,6,7,8-hexaCDD and 0.0035 per year for 1,2,3,4,6,7,8-heptaCDD. For furans the average decrease is 0.0033 per year. The elimination rates were estimated both from a longitudinal and a cross-sectional data set, and agreed quite well with each other, after taking account of historical changes in average intake levels.

Exposure to dioxin and nonneoplastic mortality in the expanded IARC international cohort study of phenoxy herbicide and chlorophenol production workers and sprayers.

The authors studied noncancer mortality among phenoxyacid herbicide and chlorophenol production workers and sprayers included in an international study comprising 36 cohorts from 12 countries followed from 1939 to 1992. Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin or higher chlorinated dioxins (TCDD/HCD) was discerned from job records and company questionnaires with validation by biologic and environmental measures. Standard mortality ratio analyses suggested a moderate healthy worker effect for all circulatory diseases, especially ischemic heart disease, among both those exposed and those not exposed to TCDD/HCD. In Poisson regression analyses, exposure to TCDD/HCD was not associated with increased mortality from cerebrovascular disease. However, an increased risk for circulatory disease, especially ischemic heart disease (rate ratio [RR] 1.67, 95% confidence interval [Cl] 1.23-2.26) and possibly diabetes (RR 2.25, 95% Cl 0.53-9.50), was present among TCDD/HCD-exposed workers. Risks tended to be higher 10 to 19 years after first exposure and for those exposed for a duration of 10 to 19 years. Mortality from suicide was comparable to that for the general population for all workers exposed to herbicides or chlorophenols and was associated with short latency and duration of exposure. More refined investigations of the ischemic heart disease and TCDD/HCD exposure association are warranted.

Quantitative cancer risk assessment for dioxins using an occupational cohort.

We consider a cohort of 1189 male German factory workers (production period 1952-1984) who produced phenoxy herbicides and were exposed to dioxins. Follow-up until the end of 1992 yielded a significantly increased standardized mortality ratio (SMR) for total cancer (SMR 141; 95% confidence interval 117-168). 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) concentrations up to 2252 ng/kg body fat were measured in 275 cohort members. Other higher chlorinated dioxins and furans also occurred in high concentrations. For quantitative analysis, the integrated TCDD concentration over time was used as an exposure variable, which was calculated using results from half-life estimation for TCDD and workplace history data. The other congeners were expressed as toxic equivalency (TEQ) and compared to TCDD using international toxic equivalency factors. Poisson and Cox regressions were used to investigate dose-response relationships. Various covariables (e.g., exposure to beta-hexachlorocyclohexane, employment characteristics) were considered. In all analyses, TCDD and TEQ exposures were related to total cancer mortality. The power model yielded a relative risk (RR) function RR(x) = (1 + 0.17x)0.326 for TCDD (in microgram/kilogram blood fat x years)--only a slightly better fit than a linear RR function--and RR(x) = (1 + 0.023x)0.795 for TEQ. Investigations on latency did not show strong effects. Different methods were applied to investigate the robustness of the results and yielded almost identical results. The results were used for unit risk estimation. Taking into account different sources of variation, an interval of 10(-3) to 10(-2) for the additional lifetime cancer risk under a daily intake of 1 pg TCDD/kg body weight/day was estimated from the dose-response models considered. Uncertainties regarding the dose-response function remain. These data did not indicate the existence of a threshold value; however, such a value cannot be excluded with any certainty.

Estimation of the cumulated exposure to polychlorinated dibenzo-p-dioxins/furans and standardized mortality ratio analysis of cancer mortality by dose in an occupationally exposed cohort.

For a cohort of 1189 male German former herbicide and insecticide workers with exposure to polychlorinated dibenzo-p-dioxins and -furans (PCDD/F), we report an extended standardized mortality ratio (SMR) analysis based on a new quantitative exposure index. This index characterizes the cumulative lifetime exposure by integrating the estimated concentration of PCDD/F at every point in time (area under the curve). Production department-specific dose rates were derived from blood levels and working histories of 275 workers by applying a first-order kinetic model. These dose rates were used to estimate exposure levels for all cohort members. Total mortality was elevated in the cohort; 413 deaths yielded an SMR of 1.15 (95% confidence interval [Cl] 1.05, 1.27) compared to the mortality of the population of Germany. Overall cancer mortality (n = 124) was significantly increased (SMR = 1.41, 95% Cl 1.17, 1.68). Various cancer sites showed significantly increased SMRs. The exposure index was used for an SMR analysis of total cancer mortality by dose. For 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) a significant trend (p = 0.01) for the SMRs with increasing cumulative PCDD/F exposure was observed. The SMR in the first exposure quartile (0-125.2 ng/kg x years) was 1.24 (95% Cl 0.82, 1.79), increasing to 1.73 (95% Cl 1.21, 2.40) in the last quartile (> or = 2503.0 ng/kg x years). For all congeners combined as toxic equivalencies (TEQ) using international toxic equivalency factors, a significant increase in cancer mortality was observed in the second quartile (360.9-1614.4 ng/kg x years, SMR 1.64; 95% Cl 1.13, 2.29) and the fourth quartile (> or = 5217.7 ng/kg x years TEQ, SMR 1.64, 95% Cl 1.13, 2.29). The trend test was not significant. The results justify the use of this cohort for a quantitative risk assessment for TCDD and to a lesser extent for TEQ.

Immunologic findings in workers formerly exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin and its congeners.

One hundred ninety-two workers in a German pesticide factory who were exposed to polychlorinated dibenzodioxins and -furans (PCDD/PCDF) were investigated for former and present diseases and laboratory changes of the immune system. Moreover, in a subgroup of 29 highly exposed and 28 control persons, proliferation studies were performed. In addition to assays such as blood count, immunoglobulins, serum electrophoresis, monoclonal bands, surface markers, autoantibodies, and lymphocyte proliferation, two new methods, the rise of tetanus antibody concentration after vaccination and the in vitro resistance of lymphocytes to chromate, were used to diagnose the morphologic and functional state of the immune system. There was no stringent correlation of actual PCDD/PCDF concentrations with the occurrence of infections or with one of the immune parameters. In addition, outcomes of the tetanus vaccination and the chromate resistance test were not correlated with PCDD/PCDF. However, the chromate resistance of lymphocytes stimulated by phytohemagglutinin of highly exposed persons was significantly lower than that for the control group. These findings indicate that the function of lymphocytes can be stressed and possibly impaired by high exposure to PCDD/PCDF.

Immune cell functions in industrial workers after exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin: dissociation of antigen-specific T-cell responses in cultures of diluted whole blood and of isolated peripheral blood mononuclear cells.

A comparative analysis was performed of the phenotype and function of peripheral blood leukocytes of two age-matched cohorts of industrial workers in chemical plants, one of which was exposed occupationally to high concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Median actual TCDD burdens were 116 ng/kg and 4 ng/kg, respectively. The phenotype analysis of peripheral blood mononuclear cells (PBMC) revealed no significant differences in the proportions of CD3, CD4, or CD8+ T lymphocytes, of CD16+ natural killer cells, and of CD19+ B lymphocytes. However, in PBMC of the TCDD-exposed workers; the proportion of CD8+ memory T cells (CD45R0+) was significantly higher, and that of lymphocytes with naive phenotype (CD45RA+) was significantly lower than in PBMC of the control group. Polyclonal and antigen-specific T-cell activation was assessed in parallel in isolated PBMC as well as in diluted whole blood cultures. In both culture systems the polyclonally stimulated cytokine release did not differ significantly between the two cohorts; however, we found a significantly reduced interferon gamma release in diluted whole blood cultures but not in isolated PBMC cultures of the TCDD-exposed cohort when we performed an antigen-specific T-cell stimulation with tetanus-toxoid. Therefore, we propose that exposure of individuals to high doses of TCDD can partially impair in the "blood milieu" those T-cell/monocyte interactions that are essential for antigen-specific T-cell responses, whereas isolated PBMC of the same donors appear functionally less affected.

Cancer mortality in workers exposed to phenoxy herbicides, chlorophenols, and dioxins. An expanded and updated international cohort study.

The authors examined cancer mortality in a historical cohort study of 21,863 male and female workers in 36 cohorts exposed to phenoxy herbicides, chlorophenols, and dioxins in 12 countries. Subjects in this updated and expanded multinational study coordinated by the International Agency for Research on Cancer were followed from 1939 to 1992. Exposure was reconstructed using job records, company exposure questionnaires, and serum and adipose tissue dioxin levels. Among workers exposed to phenoxy herbicides contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or higher chlorinated dioxins, mortality from soft-tissue sarcoma (6 deaths; standardized mortality ratio (SMR) = 2.03, 95% confidence interval (CI) 0.75-4.43) was higher than expected from national mortality rates. Mortality from all malignant neoplasms (710 deaths; SMR = 1.12, 95% CI 1.04-1.21), non-Hodgkin's lymphoma (24 deaths; SMR = 1.39, 95% CI 0.89-2.06), and lung cancer (225 deaths; SMR = 1.12, 95% CI 0.98-1.28) was slightly elevated. Risks for all neoplasms, for sarcomas, and for lymphomas increased with time since first exposure. In workers exposed to phenoxy herbicides with minimal or no contamination by TCDD and higher chlorinated dioxins, mortality from all neoplasms (398 deaths; SMR = 0.96, 95% CI 0.87-1.06), non-Hodgkin's lymphoma (9 deaths; SMR = 1.00), and lung cancer (148 deaths; SMR = 1.03) was similar to that expected, and mortality from soft-tissue sarcoma was slightly elevated (2 deaths; SMR = 1.35). In a Poisson regression analysis, workers exposed to TCDD or higher chlorinated dioxins had an increased risk for all neoplasms (rate ratio = 1.29, 95% CI 0.94-1.76) compared with workers from the same cohort exposed to phenoxy herbicides and chlorophenols but with minimal or no exposure to TCDD and higher chlorinated dioxins. These findings indicate that exposure to herbicides contaminated with TCDD and higher chlorinated dioxins may be associated with a small increase in overall cancer risk and in risk for specific cancers.

Elimination of beta-hexachlorocyclohexane in occupationally exposed persons.

The elimination of beta-hexachlorocyclohexane (beta-HCH) in humans was investigated in a group of 40 former workers of a lindane-producing plant by analyzing at least 2 blood specimens (3 specimens in 3 workers) from different time points. Assuming a first-order kinetic model for excretion, the median half-life of beta-HCH is 7.2 yr calculated by concentrations in whole blood and 7.6 yr calculated by concentrations in extractable lipids. In univariate analyses an influence of age, percent body fat, and liver disease (additionally in whole blood an influence of contents of extractable lipids) on clearance was observed. All factors show a positive correlation with half-life. According to a multiple regression model, influence of percent body fat calculated according to Deurenberg et al. (1991) is an important covariate in the description of the variations of the clearance rate (calculated on the basis of extractable lipids) of beta-HCH. The data support the assumption of first-order kinetics.

Analyses of exposure to polychlorinated dibenzo-p-dioxins, furans, and hexachlorocyclohexane and different health outcomes in a cohort of former herbicide-producing workers in Hamburg, Germany.

Several studies have been conducted to assess the exposure of a cohort of former herbicide-producing workers to PCDD/F and other potential carcinogenic substances and to evaluate the morbidity and mortality, especially for cancer, but also for other causes of death. For a quantitative dose-response analyses, a PCDD/F-blood exposure indicator was constructed from available blood levels for n = 190 workers and its relation to the working times in 14 different production departments. These indicators were used in Cox-regression models relating total cancer mortality to estimated TEQ at the end of exposure. A significant trend was observed for total cancer mortality and estimated TEQ levels at the end of exposure. The form of the dose response curve appeared to be slightly sublinear in the observed dose range. For all cardiovascular diseases (CVD), a numerical increase in risk was first observed in the third quintile of the exposure indicator 39.6-98.9 ng/kg; (RR 1.20; 0.82, 1.76), increasing to 1.70 (1.02, 2.85) in the last decile (545.1-4,361.9 ng/kg). For IHD a numerical increase was first observed in the group with TEQ ranging from 278.6 to 545.0 ng/kg (RR 1.26; 0.67, 2.39). In the highest decile, a RR of 2.17 (1.18, 4.00) was observed. The trend tests were significant for both outcomes. Unlike for cancer for CVD and IHD no increase in risk was observed in the lower dose ranges.

Cancer mortality in German male workers exposed to phenoxy herbicides and dioxins.

In an occupational cohort study, the relation between exposure to phenoxy herbicides, and contaminants (dioxins and furans) and cancer mortality was investigated. A total of 2,479 workers from four plants in Germany were included, with a mortality follow-up until the end of 1989 (for one cohort, until the end of 1992). A total of 484 deaths were recorded yielding a standardized mortality ratio (SMR) of 101 (95 percent confidence interval [CI] = 92-111) for total mortality, and an SMR of 119 (CI = 100-141) for all malignant diseases. A variety of herbicides was produced, including those which are known to have been contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). High dioxin and furan exposure (in particular, exposure to TCDD, but also to higher chlorinated dioxins) had occurred in two of the four plants as shown by blood-fat measurements in a sample of workers. Mortality from all neoplasms increased with latency and was highest in the largest plant where the highest TCDD blood levels were recorded. An increased mortality in the total cohort from respiratory cancer (SMR = 154, CI = 115-202), cancer of the buccal cavity and pharynx (SMR = 295, CI = 135-560), and non-Hodgkin's lymphoma (SMR = 326, CI = 119-710) was observed. Our findings are consistent with results from other cohorts which showed an increased overall cancer mortality and mortality of respiratory cancer after long-term exposure to these phenoxy herbicides and dioxins.