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Trace elements such as cadmium, arsenic, zinc or selenium increase or decrease risk of a wide range of human diseases. Their levels in toenails may provide a measure of mid-term intake of trace elements for studies in humans. However, in biologically and clinically aggressive diseases as pancreatic cancer, the progression of the disease could modify such concentrations and produce reverse causation bias. The aim was to analyze the influence of specific time intervals between several clinical events and the collection of toenails upon concentrations of trace elements in patients with pancreatic cancer. Subjects were 118 incident cases of pancreatic adenocarcinoma prospectively recruited in eastern Spain. Toenails were collected at cancer diagnosis, and soon thereafter interviews were conducted. Information on cancer signs and symptoms was obtained from medical records and patient interviews. Levels of 12 trace elements were determined in toenail samples by inductively coupled plasma mass spectrometry. General linear models adjusting for potential confounders were applied to analyze relations between log concentrations of trace elements and the time intervals, including the interval from first symptom of cancer to toenail collection (iST). Toenail concentrations of the 12 trace elements were weakly or not influenced by the progression of the disease or the diagnostic procedures. Concentrations of aluminum were slightly higher in subjects with a longer iST (age, sex and stage adjusted geometric means: 11.44 vs. 7.75 µg/g for iST > 120 days vs. ≤ 40 days). There was a weak inverse relation of iST with concentrations of zinc and selenium (maximum differences of about 20 and 0.08 µg/g, respectively). Conclusions: concentrations of the trace elements were weakly or not influenced by the development of the disease before toenail collection. Only concentrations of aluminum increased slightly with increasing iST, whereas levels of zinc and selenium decreased weakly. Even in an aggressive disease as pancreatic cancer, toenail concentrations of trace elements may provide a valid measure of mid-term intake of trace elements, unaffected by clinical events and disease progression. Supplementary Information The online version contains supplementary material available at 10.1007/s12403-021-00436-2.

Background: There is wide, largely unexplained heterogeneity in immunological and clinical responses to SARS-CoV-2 infection. Numerous environmental chemicals, such as persistent organic pollutants (POPs) and chemical elements (including some metals, essential trace elements, rare earth elements, and minority elements), are immunomodulatory and cause a range of adverse clinical events. There are no prospective studies on the effects of such substances on the incidence of SARS-CoV-2 infection and COVID-19. Objective: To investigate the influence of blood concentrations of POPs and elements measured several years before the pandemic on the development of SARS-CoV-2 infection and COVID-19 in individuals from the general population. Methods: We conducted a prospective cohort study in 154 individuals from the general population of Barcelona. POPs and elements were measured in blood samples collected in 2016-2017. SARS-CoV-2 infection was detected by rRT-PCR in nasopharyngeal swabs and/or by antibody serology using eighteen isotype-antigen combinations measured in blood samples collected in 2020-2021. We analyzed the associations between concentrations of the contaminants and SARS-CoV-2 infection and development of COVID-19, taking into account personal habits and living conditions during the pandemic. Results: Several historically prevalent POPs, as well as arsenic, cadmium, mercury, and zinc, were not associated with COVID-19, nor with SARS-CoV-2 infection. However, DDE (adjusted OR = 5.0 [95% CI: 1.2-21]), lead (3.9 [1.0-15]), thallium (3.4 [1.0-11]), and ruthenium (5.0 [1.8-14]) were associated with COVID-19, as were tantalum, benzo(b)fluoranthene, DDD, and manganese. Thallium (3.8 [1.6-8.9]), and ruthenium (2.9 [1.3-6.7]) were associated with SARS-CoV-2 infection, and so were lead, gold, and (protectively) iron and selenium. We identified mixtures of up to five substances from several chemical groups, with all substances independently associated to the outcomes. Conclusions: Our results provide the first prospective and population-based evidence of an association between individual concentrations of some contaminants and COVID-19 and SARS-CoV-2 infection. POPs and elements may contribute to explain the heterogeneity in the development of SARS-CoV-2 infection and COVID-19 in the general population. If the associations are confirmed as causal, means are available to mitigate the corresponding risks.

Background Findings and limitations of previous studies on persistent organic pollutants (POPs) and pancreatic cancer risk support conducting further research in prospective cohorts. Objective To investigate the association between plasma concentrations of selected POPs and pancreatic cancer risk. Methods Prospective case-control study nested within the EPIC cohort. Participants were 513 pancreatic cancer cases and 1020 matched controls. Concentrations of 22 POPs (organochlorine pesticides, polychlorinated biphenyls, and polybrominated diphenyl ethers) were measured in plasma collected at baseline by GC-MS/MS. Results Some, generally moderate effects were observed at higher concentrations of p,p’-DDT, trans-nonachlor, β-hexachlorocyclohexane, and the sum of 6 organochlorine pesticides and of 16 POPs. The odds ratio (OR) for the upper quartile of trans-nonachlor was 1.55 (95% confidence interval 1.06 to 2.26; P for trend=0.025). Associations were stronger in the groups predefined as most valid or relevant. Among participants having fasted >6 hours at blood collection, the ORs were significant for 10 of 11 exposure categories. Higher ORs were also observed among cases with microscopic confirmation than in cases with a clinical diagnosis. Higher ORs were also observed among normal-weight participants, with relevant estimates for all 11 exposure categories. Among participants with a follow-up ≥10 years, estimates were also higher (e.g., for trans-nonachlor: OR = 2.14, 1.01 to 4.53, P for trend=0.035). Overall, trans-nonachlor, 3 PCBs, and the 2 sums of POPs were the exposures more clearly associated with pancreatic cancer risk. Conclusions A few moderately increased risks were apparent for the highest concentrations of certain POPs, sometimes with a dose-response relationship.

Background Findings and limitations of previous studies on persistent organic pollutants (POPs) and pancreatic cancer risk support conducting further research in prospective cohorts. Methods We conducted a prospective case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Participants were 513 pancreatic cancer cases and 1020 matched controls. Concentrations of 22 POPs were measured in plasma collected at baseline. Results Some associations were observed at higher concentrations of p, p’-DDT, trans-nonachlor, β-hexachlorocyclohexane and the sum of six organochlorine pesticides and of 16 POPs. The odds ratio (OR) for the upper quartile of trans-nonachlor was 1.55 (95% confidence interval 1.06-2.26; P for trend = 0.025). Associations were stronger in the groups predefined as most valid (participants having fasted >6 h, with microscopic diagnostic confirmation, normal weight, and never smokers), and as most relevant (follow-up ≥10 years). Among participants having fasted >6 h, the ORs were relevant for 10 of 11 exposures. Higher ORs were also observed among cases with microscopic confirmation than in cases with a clinical diagnosis, and among normal-weight participants than in the rest of participants. Among participants with a follow-up ≥10 years, estimates were higher than in participants with a shorter follow-up (for trans-nonachlor: OR = 2.14, 1.01 to 4.53, P for trend = 0.035). Overall, trans-nonachlor, three PCBs and the two sums of POPs were the exposures most clearly associated with pancreatic cancer risk. Conclusions Individually or in combination, most of the 22 POPs analysed did not or only moderately increased the risk of pancreatic cancer.

OBJECTIVE: To explore factors influencing perceptions and viewpoints on the responsibility for the presence of toxic substances in food, on enforcement of laws and regulations that control human exposure to toxic substances in food, and on the effectiveness of such regulations. METHODS: An online survey was completed by 740 individuals from several parts of Spain (median age, 47 years; 67% were women; 70% had completed university studies). RESULTS: Over 87% of respondents said that it was possible that throughout their lives they could have accumulated in their body toxic substances potentially dangerous to their health. The attribution of the responsibility for toxic substances in food to a larger number of social groups was more frequent among respondents who consulted information about the problem more often (odds ratio [OR]: 1.92), who correctly identified factors that increase the likelihood of toxic substances in food being harmful to human health (OR: 2.86), who better knew the health problems that may be caused by such substances (OR: 2.48), and who recognised more food groups that tend to have concentrations of toxic substances potentially harmful to health (OR: 2.92) (all p values

Factors underlying metabolic phenotypes, such as the metabolically healthy but obese phenotype, remain unclear. Differences in metabolic phenotypes-particularly, among individuals with a similar body mass index-could be related to concentrations of persistent organic pollutants (POPs). To our knowledge, no studies have analyzed POPs and metabolic phenotypes in normal-weight persons. We investigated the relationships between serum concentrations of POPs and metabolic phenotypes in 860 normal-weight, overweight, and obese participants in the 2002 Catalan Health Interview Survey (Spain). POP concentrations were significantly higher in metabolically unhealthy than in metabolically healthy individuals. In models adjusting for body mass index and other confounders, hexachlorobenzene, β-hexachlorocyclohexane, and polychlorinated biphenyls were associated with the unhealthy metabolic phenotype and metabolic syndrome. Among normal-weight individuals, the adjusted prevalence ratio of having an unhealthy phenotype for the upper category of the sum of orders of the 6 mentioned POPs (all individually associated with metabolic phenotypes) was 4.1 (95% confidence interval: 1.7, 10.0). Among overweight and obese individuals, the corresponding prevalence ratio for the sum of polychlorinated biphenyls was 1.4 (95% confidence interval: 1.0, 1.8). Our results supported the hypothesis that POP concentrations are associated with unhealthy metabolic phenotypes, not only in obese and overweight individuals but also (and probably more strongly) in normal-weight individuals.

Background: Some occupations potentially entailing exposure to cadmium, arsenic, lead, selenium, nickel, and chromium have been associated with an increased risk of exocrine pancreatic cancer (EPC), but no studies have assessed whether body concentrations of such compounds differed among subjects occupationally exposed and unexposed. No studies which found that exposure to such metals increased the risk of EPC assessed whether past occupations were the source of exposure. Objective: The aim was to analyse the relationship between toenail concentrations of trace elements and occupational history in EPC patients. Methods: The study included 114 EPC cases personally interviewed on occupational history and lifestyle factors. Occupations were coded according to the International Standard Classification of Occupations 1988. Selected occupational exposures were assessed by two industrial hygienists and with the Finnish job-exposure matrix (Finjem). Concentrations of 12 trace elements were determined in toenail samples by inductively coupled plasma mass spectrometry. Adjusted geometric means (aGMs) and 95% confidence intervals (95% CI) were calculated. Results: Patients occupationally exposed to aromatic hydrocarbon solvents (AHs) had higher concentrations of cadmium, manganese, lead, iron and vanadium. The aGM of cadmium concentrations for cases exposed to any pesticide was 0.056 μg/g [95% CI: 0.029–0.108], and, for unexposed cases, 0.023 μg/g [0.017–0.031]. Patients occupationally exposed to pesticides had higher concentrations of cadmium and manganese. Higher concentrations of vanadium, lead and arsenic were related to exposure to formaldehyde. Vanadium and lead were also associated with exposure to chlorinated hydrocarbon solvents, and arsenic was related to exposure to polycyclic aromatic hydrocarbons (PAHs). Conclusions: Patients occupationally exposed to AHs, pesticides, chlorinated hydrocarbon solvents, formaldehyde, volatile sulphur compounds and PAHs had higher concentrations of several metals. These elements may account for some of the occupational risks previously reported for pancreatic cancer., This work was partly supported by research grants from Instituto de Salud Carlos III, Ministry of Health, Government of Spain (FIS PI13/00020, FIS PI17/00088, and CIBER de Epidemiologia y Salud Publica - CIBERESP); the Hospital del Mar Medical Research Institute (IMIM), Barcelona; Fundacio La Marato de TV3 (20132910); and the Government of Catalonia (2009 SGR 1350, 2014 SGR 1012, 2017 SGR 439). The Dartmouth Trace Element Core was partially supported by NIH Grant Number P42 ES007373 from the National Institute of Environmental Health Sciences.

Trace elements are a possible risk factor for pancreatic ductal adenocarcinoma (PDAC). However, their role in the occurrence and persistence of KRAS mutations remains unstudied. There appear to be no studies analyzing biomarkers of trace elements and KRAS mutations in any human cancer. We aimed to determine whether patients with KRAS mutated and nonmutated tumors exhibit differences in concentrations of trace elements. Incident cases of PDAC were prospectively identified in five hospitals in Spain. KRAS mutational status was determined through polymerase chain reaction from tumor tissue. Concentrations of 12 trace elements were determined in toenail samples by inductively coupled plasma mass spectrometry. Concentrations of trace elements were compared in 78 PDAC cases and 416 hospital-based controls (case-control analyses), and between 17 KRAS wild-type tumors and 61 KRAS mutated tumors (case-case analyses). Higher levels of iron, arsenic, and vanadium were associated with a statistically nonsignificant increased risk of a KRAS wild-type PDAC (OR for higher tertile of arsenic = 3.37, 95% CI 0.98-11.57). Lower levels of nickel and manganese were associated with a statistically significant higher risk of a KRAS mutated PDAC (OR for manganese = 0.34, 95% CI 0.14-0.80). Higher levels of selenium appeared protective for both mutated and KRAS wild-type PDAC. Higher levels of cadmium and lead were clear risk factors for both KRAS mutated and wild-type cases. This is the first study analyzing biomarkers of trace elements and KRAS mutations in any human cancer. Concentrations of trace elements differed markedly between PDAC cases with and without mutations in codon 12 of the KRAS oncogene, thus suggesting a role for trace elements in pancreatic and perhaps other cancers with such mutations. Environ. Mol. Mutagen., 60:693-703, 2019. © 2019 Wiley Periodicals, Inc.

Self-rated health (SRH) is a powerful predictor of mortality, morbidity, and need for health services. SRH generally increases with educational level, and decreases with age, number of chronic conditions, and body mass index (BMI). Because human concentrations of most persistent organic pollutants (POPs) also vary by age, education, and BMI, and because of the physiological and clinical effects of POPs, we hypothesized that body concentrations of POPs are inversely associated with SRH.To analyze the relation between serum concentrations of POPs and SRH in the general population of Catalonia, Spain, taking into account sociodemographic factors and BMI, as well as chronic health conditions and mental disorders, measured by the General Health Questionnaire-12 (GHQ-12).POP serum concentrations were measured by gas chromatography with electron-capture detection in 919 participants of the Catalan Health Interview Survey.Individuals with higher concentrations of POPs had significantly poorer SRH; e.g., the median concentration of HCB in subjects with poor SRH was twice as high as in subjects with excellent SRH (366 ng/g vs. 169 ng/g, respectively; p-value0.001). In crude models and in models adjusted for sex and BMI, the POPs-SRH association was often dose-dependent, and the likelihood of poor or regular SRH was 2 to 4-times higher in subjects with POP concentrations in the top quartile. In models adjusted for age or for chronic conditions virtually all ORs were near unity. No associations were found between POP levels and GHQ-12.Individuals with higher concentrations of POPs had significantly poorer SRH, an association likely due to age and chronic conditions, but not to sex, education, social class, BMI, or mental disorders.

Background: The use of biomarkers of environmental exposure to explore new risk factors for pancreatic cancer presents clinical, logistic, and methodological challenges that are also relevant in research on other complex diseases.Objectives: First, to summarize the main design features of a prospective case-control study –nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort– on plasma concentrations of persistent organic pollutants (POPs) and pancreatic cancer risk. And second, to assess the main methodological challenges posed by associations among characteristics and habits of study participants, fasting status, time from blood draw to cancer diagnosis, disease progression bias, basis of cancer diagnosis, and plasma concentrations of lipids and POPs. Results from etiologic analyses on POPs and pancreatic cancer risk, and other analyses, will be reported in future articles.Methods: Study subjects were 1533 participants (513 cases and 1020 controls matched by study centre, sex, age at blood collection, date and time of blood collection, and fasting status) enrolled between 1992 and 2000. Plasma concentrations of 22 POPs were measured by gas chromatography - triple quadrupole mass spectrometry (GC-MS/MS). To estimate the magnitude of the associations we calculated multivariate-adjusted odds ratios by unconditional logistic regression, and adjusted geometric means by General Linear Regression Models.Results: There were differences among countries in subjects’ characteristics (as age, gender, smoking, lipid and POP concentrations), and in study characteristics (as time from blood collection to index date, year of last follow-up, length of follow-up, basis of cancer diagnosis, and fasting status). Adjusting for centre and time of blood collection, no factors were significantly associated with fasting status. Plasma concentrations of lipids were related to age, body mass index, fasting, country, and smoking. We detected and quantified 16 of the 22 POPs in more than 90% of individuals. All 22 POPs were detected in some participants, and the smallest number of POPs detected in one person was 15 (median, 19) with few differences by country. The highest concentrations were found for p,p’-DDE, PCBs 153 and 180 (median concentration: 3371, 1023, and 810 pg/mL, respectively). We assessed the possible occurrence of disease progression bias (DPB) in eight situations defined by lipid and POP measurements, on one hand, and by four factors: interval from blood draw to index date, tumour subsite, tumour stage, and grade of differentiation, on the other. In seven of the eight situations results supported the absence of DPB.Conclusions: The coexistence of differences across study centres in some design features and participant characteristics is of relevance to other multicentre studies. Relationships among subjects’ characteristics and among such characteristics and design features may play important roles in the forthcoming analyses on the association between plasma concentrations of POPs and pancreatic cancer risk.

In clinically aggressive diseases, patients experience pathophysiological changes that often alter concentrations of lipids and environmental lipophilic factors; such changes are related to disease signs and symptoms. The aim of the study was to compare the effects of correcting for total serum lipids (TSL) and other clinical factors on the odds of mutations in the K-ras oncogene by organochlorine compounds (OCs), in logistic models, in 103 patients with exocrine pancreatic cancer (EPC) using a causal directed acyclic graph (DAG) framework. Results and likelihood of bias were discussed in the light of possible causal scenarios. The odds of K-ras mutated EPC was associated with some TSL-corrected OCs, including p,p'-DDT (p-value: 0.008) and polychlorinated biphenyl 138 (p-trend: 0.024). When OCs were not corrected by TSL, the OR of a K-ras mutation was significant for p,p'-DDT (p-trend: 0.035). Additionally adjusting for cholestatic syndrome increased the ORs of TSL-corrected OCs. When models were adjusted by the interval from first symptom to blood extraction (ISE), the ORs increased for both TSL-corrected and uncorrected OCs. Models with TSL-corrected OCs and adjusted for cholestatic syndrome or ISE yielded the highest ORs. We show that DAGs clarify the covariates necessary to minimize bias, and demonstrate scenarios under which adjustment for TSL-corrected OCs and failure to adjust for symptoms or ISE may induce bias. Models with TSL-uncorrected OCs may be biased too, and adjusting by symptoms or ISE may not control such biases. Our findings may have implications as well for studying environmental causes of other clinically aggressive diseases.

Background: Australian national biomonitoring for persistent organic pollutants (POPs) relies upon age-specific pooled serum samples to characterize central tendencies of concentrations but does not provide estimates of upper bound concentrations. This analysis compares population variation from biomonitoring datasets from the US, Canada, Germany, Spain, and Belgium to identify and test patterns potentially useful for estimating population upper bound reference values for the Australian population. Methods: Arithmetic means and the ratio of the 95th percentile to the arithmetic mean (P95:mean) were assessed by survey for defined age subgroups for three polychlorinated biphenyls (PCBs 138, 153, and 180), hexachlorobenzene (HCB), p,p-dichlorodiphenyldichloroethylene (DDE), 2,2′,4,4′ tetrabrominated diphenylether (PBDE 47), perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). Results: Arithmetic mean concentrations of each analyte varied widely across surveys and age groups. However, P95:mean ratios differed to a limited extent, with no systematic variation across ages. The average P95:mean ratios were 2.2 for the three PCBs and HCB; 3.0 for DDE; 2.0 and 2.3 for PFOA and PFOS, respectively. The P95:mean ratio for PBDE 47 was more variable among age groups, ranging from 2.7 to 4.8. The average P95:mean ratios accurately estimated age group-specific P95s in the Flemish Environmental Health Survey II and were used to estimate the P95s for the Australian population by age group from the pooled biomonitoring data. Conclusions: Similar population variation patterns for POPs were observed across multiple surveys, even when absolute concentrations differed widely. These patterns can be used to estimate population upper bounds when only pooled sampling data are available. Keywords: Persistent organic pollutants, Biomonitoring, Variation, Population monitoring

Objectives To analyze whether differences between the interval from suspicion or clinical diagnosis to treatment onset (IClinDT) and the interval from certainty diagnosis to treatment onset (ICertDT) varied by tumor site, stage, and mode of hospital admission. Study Design and Setting From our hospital cancer registry, we selected all 8,814 patients with breast, colorectal, lung, prostate, or cervical cancer diagnosed between 1992 and 2006. We compared IClinDT and ICertDT with density plots and logistic regression. Results IClinDT was up to three times higher than ICertDT. There were very large differences among stages and within each stage in IClinDT and ICertDT. Tumor stage significantly influenced the difference between the two intervals in three of the five locations (breast, lung, and prostate cancer); as stage worsened, the difference between IClinDT and ICertDT became smaller. In all tumor sites, the difference was larger in scheduled than in emergency admissions. Overall, therapeutic delays—even when measured by ICertDT—were disturbingly common for important subgroups of patients. Conclusion The difference between IClinDT and ICertDT varied highly by tumor site, stage, and mode of hospital admission. More standardized definitions and procedures to calculate time intervals between cancer diagnosis and treatment onset are needed.

There is increasing evidence that environmental factors play an important role in the development of type 2 diabetes. Several persistent organic pollutants are suspected to contribute to the increasing prevalence and risk of type 2 diabetes. The aim of this study was to investigate the association of the body burden of three organochlorine pesticides and three polychlorinated biphenyls and the overall estrogenic activity with the risk of type 2 diabetes in a sample of adults from Southern Spain. Samples of adipose tissue and serum were obtained from 386 subjects undergoing non-cancer-related surgery and were extracted using validated methodologies. Residues of persistent organic pollutants were analyzed by means of high-resolution gas chromatography with a mass spectrometry detector in tandem mode. The overall estrogenicity of the adipose tissue extracts was measured by using the total effective xenoestrogen burden (TEXB) biomarker. Data on lifestyle, dietary habits, and health status were gathered from face-to-face interviews and clinical records. Statistical analyses were performed with unconditional logistic regression and different adjustment levels. In the models adjusted for adipose tissue origin, sex, age, and body mass index, the 2nd and 3rd tertiles of adipose tissue concentrations of p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) were positively associated with the risk of diabetes [odds ratios (95% confidence interval)=3.6 (0.8-17.3) and 4.4 (1.0-21.0), respectively]. A positive association with β-hexachlorocyclohexane was also found when body mass index and adipose tissue origin were removed from the models, with odds ratios (95% confidence interval) of 3.3 (1.0-10.4) and 5.5 (1.7-17.3), for the 2nd and 3rd tertiles of exposure, respectively. In addition, a statistically significant interaction was observed between p,p'-DDE and body mass index, such that the risk of diabetes increased with tertiles of exposure in a linear manner in non-obese subjects but not in the obese, in whom an inverted U-shape pattern was observed.

We aimed to assess changes in the total effective xenoestrogen burden (TEXB) -a biomarker of combined effect of mixtures of xenoestrogens- in breast cancer patients at surgery (breast adipose tissue) and at different time points during an 18-month follow-up (abdominal adipose tissue), and to analyze the potential influence of socio-demographic, reproductive, tumor, and treatment characteristics on TEXB levels. TEXB-alpha (due to persistent organohalogenated chemicals) and TEXB-beta (due mainly to endogenous estrogens) were quantified in 44 women. TEXB values significantly increased over follow-up (p

Background: Surveys of human exposure to environmental chemicals do not integrate the number of compounds detected per person and the concentration of each compound. This leaves untested relevant exposure scenarios, such as whether individuals with low concentrations of some compounds have high concentrations of the other compounds. Objective: To analyze the number of persistent organic pollutants (POPs) detected at high concentrations. Methods: Serum concentrations of 19 POPs were analyzed by gas chromatography with electron-capture detection in a representative sample of the general population of Catalonia, Spain (N=919). Results: Over 58% of participants had concentrations in the top quartile of ≥1 of the eight most prevalent POPs, and 34% of ≥3 POPs. 83% of women 60 to 74 years old had concentrations of ≥3 POPs in the top quartile; 56% of women 60 to 74 years had p,p′-DDE, HCB and β-HCH all in their respective top quartiles, and 48% had concentrations of ≥6 POPs in the top quartile. Over 30% of subjects had concentrations in the top decile of 1 to 5 of the eight most prevalent POPs. Half of the population had levels of 1 to 5 POPs >500 ng/g. Less than 4% had all eight POPs in the lowest quartile. Conclusions: More than half of the study population had concentrations in the top quartile of ≥1 POPs. Significant subgroups of the population accumulate POP mixtures at high concentrations. POP concentrations appear low in most of the population only when each individual compound is looked at separately. Keywords: Human biomonitoring, Health survey, Persistent organic pollutants, Environmental pollutants/prevention and control, Environmental exposure/adverse effects

The aim was to analyze the effects of body mass index (BMI), low-dose exposure, mixtures of persistent organic pollutants (POPs), and lipid adjustment on the relationship between POP concentrations and diabetes and prediabetes in the general adult population of Catalonia (Spain). Serum concentrations of POPs were measured by gas chromatography with electron-capture detection in 886 participants in a health interview survey. The highest concentrations of all POPs analyzed were found in subjects who had diabetes. Levels were also higher in individuals with prediabetes than in subjects without the disorder. In models adjusted by age, sex and BMI, the prevalence of diabetes and prediabetes increased in a dose-dependent manner across quartiles of PCBs 118, 138, 153, and 180, and HCB. When models were further adjusted for lipids, the associations were slightly lower and statistically significant, the ORs for the upper quartile ranging from 2.0 to 2.8 (all p-values for linear trend

Background: Numerous studies analyzed concentrations of persistent organic pollutants (POPs) in human samples, and in many types of foods; however, food consumption is less commonly included in studies on the determinants of POP concentrations in humans, and these approaches are rarely integrated with surveys of food intake to estimate the amount and safety of human POP intake from food. Objective: To analyze the main characteristics and findings of all studies conducted in Spain that quantitatively assessed the influence of diet on human concentrations of POPs. Methods: Studies published until December 2010 (with no other time restrictions) were identified through Medline/PubMed, ISI-Thomson, ScienceDirect, and SciELO databases. Results: We identified 25 papers, from 19 different studies. Twelve papers were published in 2009–2010. All studies but one were based on subgroups not representative of the general population, and over half were limited to women. Serum was the most used biological matrix, while p,p′-DDE, HCB and PCBs were the most frequently analyzed compounds. Food intakes were measured with heterogeneous food frequency questionnaires. The most consistent association was between fish consumption and PCBs and HCB, followed by dairy products and PCBs. A few studies observed a relationship between meat and some POPs, whilst intake of vegetables, fruits and cereals was rarely related to POP levels. Only 3 studies did not find any relationship between dietary habits and POP concentrations. Conclusions: In spite of methodological heterogeneity, the studies were able to quantify to what extent consumption of foods from animal origin (fish, milk, dairy products and meat) is related to higher body concentrations of POPs. As in a few other countries, in Spain food consumption is increasingly analyzed as a major determinant of human POP intake. Keywords: Organochlorine compounds, Food safety, Dichlorodiphenyltrichloroethane, Hexachlorobenzene, Fish, Milk

Background Little is known about factors affecting participation in population-based biomonitoring studies. We analyzed socioeconomic factors influencing participation in the Barcelona Health Survey (BHS) study on the distribution of serum concentrations of persistent organic pollutants (POPs). Methods After completing the BHS personal interview at home participants aged ⩾15 years were invited to donate blood. Conducted on a different date and location, the POPs study included additional questions, blood extraction, and a brief physical examination. Factors influencing participation were analyzed by logistic regression. Results Of 523 BHS participants that we contacted to participate in the study, 231 (44%) participated; they were broadly representative of the city population regarding sex, birth place, body mass index (BMI), employment status and occupational social class. Participants in the POPs study had higher educational level and family income. Controlling for confounders, participation was slightly higher among women than men (odds ratio [OR] = 1.38, p = 0.02), and lower among the youngest and oldest subjects (p = 0.002), with a strong and monotonic trend of increasing participation with increasing educational level (p Conclusions Although participation was somewhat low, participants were similar to the city population regarding sex, BMI, birth place, employment, and occupational social class. Health surveys that integrate environmental biomarkers should invest specific resources to encourage participation of the youngest and oldest individuals, and of those with more disadvantaged socioeconomic position (particularly, citizens with lowest education).

The frequency of CYP1B1 polymorphisms in pancreatic cancer has never been reported. There is also no evidence on the relationship between CYP1B1 variants and mutations in ras genes (K-, H- or N-ras) in any human neoplasm. We analyzed the following CYP1B1 polymorphisms in 129 incident cases of pancreatic ductal adenocarcinoma (PDA): the m1 allele (Val to Leu at codon 432) and the m2 allele (Asn to Ser at codon 453). The calculated frequencies for the m1 Val and m2 Asn alleles were 0.45 and 0.68, respectively. CYP1B1 genotypes were out of Hardy-Weinberg equilibrium; this was largely due to K-ras mutated PDA cases. The Val/Val genotype was over five times more frequent in PDA cases with a K-ras mutation than in wild-type cases (OR = 5.25; P = 0.121). In PDA, polymorphisms in CYP1B1 might be related with K-ras activation pathways.

Human exposure to environmental chemicals as persistent organic pollutants (POPs) is usually assessed considering each pollutant individually, with little attention to concentrations of mixtures in individuals or social groups. Yet, it may be relatively common for humans to have low and high concentrations of numerous POPs. The study objectives were to analyze the number of POPs detected per person at high concentrations in the U.S. population, and the associations between such type of indicators and socioeconomic factors as gender, race / ethnicity, education, and poverty level. From 91 POPs analyzed in serum samples of 4,739 individuals in three subsamples of the National Health and Nutrition Examination Survey (NHANES) 2003-2004 (the last period with valid updated individual data for the compounds considered in the present study), we computed the number of POPs whose serum concentrations were above selected cutoff points. POPs included were 13 organochlorine compounds (OCs), 10 polybrominated diphenyl ethers (PBDEs), the polybrominated biphenyl (PBB) 153, 38 polychlorinated biphenyls (PCBs), 17 polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs/Fs), and 12 perfluorinated compounds (PFCs). Over 13% of participants had ≥10 of the 37 most detected POPs each at a concentration in the top decile (P90). Over 30% of subjects with total toxic equivalency (TEQ) ≥P75, had ≥10 of 24 POPs not included in TEQ calculations at concentrations ≥P90. Compared to non-Hispanic whites, the adjusted odds ratio of having ≥10 of the 37 POPs at P90 was 9.2 for non-Hispanic blacks and 0.18 for Mexican Americans. Poverty, body mass index, age, and gender were also independently associated with having ≥10 POPs in the top decile. More than one tenth of the US population may have ≥10 POPs each at concentrations in the top decile. Such pattern is nine times more frequent in Non-Hispanic blacks and four times less frequent in Mexican Americans than in non-Hispanic whites. The work was supported in part by research grants from Instituto de Salud Carlos III –FEDER (FIS PI13/00020 and CIBER de Epidemiología y Salud Pública − CIBERESP), Government of Spain; Fundació La Marató de TV3 (20132910); and Government of Catalonia (2014 SGR 1012).

BACKGROUND: Accumulated exposure to hormones and growth factors during early life may influence the future risk of breast cancer (BC). This study examines the influence of childhood-related, socio-demographic and anthropometric variables on BC risk, overall and by specific pathologic subtypes. METHODS: This is a case-control study where 1539 histologically-confirmed BC cases (23-85 years) and 1621 population controls, frequency matched by age, were recruited in 10 Spanish provinces. Perinatal and childhood-related characteristics were directly surveyed by trained staff. The association with BC risk, globally and according to menopausal status and pathologic subtypes, was evaluated using logistic and multinomial regression models, adjusting for tumor specific risk factors. RESULTS: Birth characteristics were not related with BC risk. However, women with high socioeconomic level at birth presented a decreased BC risk (OR=0.45; 95% CI=0.29-0.70), while those whose mothers were aged over 39 years at their birth showed an almost significant excess risk of hormone receptor positive tumors (HR+) (OR=1.35; 95% CI=0.99-1.84). Women who were taller than their girl mates before puberty showed increased postmenopausal BC risk (OR=1.26; 95% CI=1.03-1.54) and increased HR+ BC risk (OR=1.26; 95% CI=1.04-1.52). Regarding prepubertal weight, while those women who were thinner than average showed higher postmenopausal BC risk (OR=1.46; 95% CI=1.20-1.78), associated with HR+ tumors (OR=1.34; 95% CI=1.12-1.61) and with triple negative tumors (OR=1.56; 95% CI=1.03-2.35), those who were heavier than average presented lower premenopausal BC risk (OR=0.64; 95% CI=0.46-0.90) and lower risk of epidermal growth factor receptor positive tumors (OR=0.61; 95% CI=0.40-0.93). CONCLUSION: These data reflect the importance of hormones and growth factors in the early stages of life, when the mammary gland is in development and therefore more vulnerable to proliferative stimuli. The authors acknowledge funds provided by the Spanish Ministry of Economy and Competitiveness (Carlos III Institute of Health; PI12/00488, PI12/00265, PI12/01270, PI12/00715, PI12/00150, PI08/1770, PI08/0533, PI08/1359, PS09/00773, PS09/01286, PS09/01903, PS09/02078, PS09/01662, PI11/01403, PI11/01889, PI11/00226, PI11/01810, PI11/02213, PI14/01219 and Rio Hortega CM13/00232), the Catalan Government 2009SGR1489 & 2014SGR756-F, and, by the Fundación Marqués de Valdecilla (API 10/09), by the ICGC International Cancer Genome Consortium CLL, by the Junta de Castilla y León (LE22A10-2), by the Consejería de Salud of the Junta de Andalucía (PI-0571), by the Conselleria de Sanitat of the Generalitat Valenciana (AP 061/10), by the Recercaixa (2010ACUP 310), by the Regional Government of the Basque Country by European Commission grants FOOD-CT-2006-036224-HIWATE, and by the Spanish Association Against Cancer (AECC) Scientific Foundation.

Analyses of the concentrations of a given environmental compound usually show that most citizens have much lower concentrations than a certain minority, whose members have high body concentrations. Surveys of human exposure to chemicals do not usually integrate the number of chemical compounds detected per person and the concentration of each compound. This leaves untested relevant exposure situations, for example, whether individuals with low concentrations of some compounds have high concentrations of the other compounds. On scientific grounds, it is puzzling that this possibility, arithmetically and conceptually rather simple, has seldom if ever been tested in studies based on a representative sample of the general population. A study based on a representative sample of the general population of Catalonia (Spain) (Porta, Pumarega,Gasull, 2012), which integrated the number of compounds detected per person and the concentration of each compound, found that more than half of the population had concentrations in the top quartile of 1 or more of the 19 persistent toxic substances (PTS) (pesticides and polychlorinated biphenyls) analyzed. Significant subgroups of the population accumulated PTS mixtures at high concentrations. For instance, 48% of women 60-74 years had concentrations of 6 or more PTS in the top quartile; half of the entire population had levels of 1-5 PTS above 500 ng/g, and less than 4% of citizens had all PTS in the lowest quartile. Thus, PTS concentrations appear low in most of the population only when each individual compound is looked at separately. It is not accurate to state that most of the population has low concentrations of PTS. The assessment of mixture effects must address the fact that most individuals are contaminated by PTS mixtures made of compounds at both low and high concentrations.

Analyses of the concentrations of a given environmental compound usually show that most citizens have much lower concentrations than a certain minority, whose members have high body concentrations. Surveys of human exposure to chemicals do not usually integrate the number of chemical compounds detected per person and the concentration of each compound. This leaves untested relevant exposure situations, for example, whether individuals with low concentrations of some compounds have high concentrations of the other compounds. On scientific grounds, it is puzzling that this possibility, arithmetically and conceptually rather simple, has seldom if ever been tested in studies based on a representative sample of the general population. A study based on a representative sample of the general population of Catalonia (Spain) (Porta, Pumarega, & Gasull, 2012), which integrated the number of compounds detected per person and the concentration of each compound, found that more than half of the population had concentrations in the top quartile of 1 or more of the 19 persistent toxic substances (PTS) (pesticides and polychlorinated biphenyls) analyzed. Significant subgroups of the population accumulated PTS mixtures at high concentrations. For instance, 48% of women 60-74 years had concentrations of 6 or more PTS in the top quartile; half of the entire population had levels of 1-5 PTS above 500 ng/g, and less than 4% of citizens had all PTS in the lowest quartile. Thus, PTS concentrations appear low in most of the population only when each individual compound is looked at separately. It is not accurate to state that most of the population has low concentrations of PTS. The assessment of mixture effects must address the fact that most individuals are contaminated by PTS mixtures made of compounds at both low and high concentrations.

Scant evidence is available worldwide on the relative influence of occupational social class and educational level on body concentrations of persistent organic pollutants (POPs) in the general population. The objective was to analyse such influence in a representative sample of the general population of Catalonia, Spain. Participants in the Catalan Health Interview Survey aged 18–74 were interviewed face-to-face, gave blood, and underwent a physical exam. The role of age, body mass index (BMI), and parity was analysed with General Linear Models, and adjusted geometric means (GMs) were obtained. Crude (unadjusted) concentrations were higher in women and men with lower education, and in women, but not men, in the less affluent social class. After adjusting for age, in women there were no associations between POP levels and social class or education. After adjusting for age and BMI, men in the less affluent class had higher p,p′-DDE concentrations than men in class I (p-value = 0.016), while men in class IV had lower HCB than men in the upper class (p-value

We analyzed relationships of hepatic and pancreatic biomarkers with the cholestatic syndrome and tumor stage in exocrine pancreatic cancer (N = 183). Information on laboratory tests and on signs and symptoms was obtained from medical records and patient interviews. Bilirubin, aspartate aminotransferase (AST), γ-glutamyltransferase (GGT) and alkaline phosphatase were lower in tumor stage IV. The association was due to the relationship between cholestatic syndrome and earlier presentation of patients. There was no association between hepatic biomarkers and stage when adjusting by cholestatic syndrome. Relationships of hepatic and pancreatic biomarkers with pancreatic symptoms and tumor stage must be controlled in “-omics” and other studies using biomarkers.

Background Both genetic and environmental factors contribute to triglyceride, low-density lipoprotein-cholesterol (LDL-C), and high-density lipoprotein-cholesterol (HDL-C) levels. Although genome-wide association studies are currently testing the genetic factors systematically, testing and reporting one or a few factors at a time can lead to fragmented literature for environmental chemical factors. We screened for correlation between environmental factors and lipid levels, utilizing four independent surveys with information on 188 environmental factors from the Centers of Disease Control, National Health and Nutrition Examination Survey, collected between 1999 and 2006. Methods We used linear regression to correlate each environmental chemical factor to triglycerides, LDL-C and HDL-C adjusting for age, age2, sex, ethnicity, socio-economic status and body mass index. Final estimates were adjusted for waist circumference, diabetes status, blood pressure and survey. Multiple comparisons were controlled for by estimating the false discovery rate and significant findings were tentatively validated in an independent survey. Results We identified and validated 29, 9 and 17 environmental factors correlated with triglycerides, LDL-C and HDL-C levels, respectively. Findings include hydrocarbons and nicotine associated with lower HDL-C and vitamin E (γ-tocopherol) associated with unfavourable lipid levels. Higher triglycerides and lower HDL-C were correlated with higher levels of fat-soluble contaminants (e.g. polychlorinated biphenyls and dibenzofurans). Nutrients and vitamin markers (e.g. vitamins B, D and carotenes), were associated with favourable triglyceride and HDL-C levels. Conclusions Our systematic association study has enabled us to postulate about broad environmental correlation to lipid levels. Although subject to confounding and reverse causality bias, these findings merit evaluation in additional cohorts.

Background and Aims Knowledge on the aetiology of exocrine pancreatic cancer (EPC) is scant. The best established risk factor for EPC is tobacco smoking. Among other carcinogens, tobacco contains cadmium, a metal previously associated with an increased risk of EPC. This study evaluated the association between concentrations of trace elements in toenails and EPC risk. Methods The study included 118 EPC cases and 399 hospital controls from eastern Spain. Levels of 12 trace elements were determined in toenail samples by inductively coupled plasma mass spectrometry. OR and 95% CI, adjusted for potential confounders, were calculated using logistic regression. Results Significantly increased risks of EPC were observed among subjects whose concentrations of cadmium (OR 3.58, 95% CI 1.86 to 6.88; p trend =5×10 −6 ), arsenic (OR 2.02, 95% CI 1.08 to 3.78; p trend =0.009) and lead (OR 6.26, 95% CI 2.71 to 14.47; p trend =3×10 −5 ) were in the highest quartile. High concentrations of selenium (OR 0.05, 95% CI 0.02 to 0.15; p trend =8×10 −11 ) and nickel (OR 0.27, 95% CI 0.12 to 0.59; p trend =2×10 −4 ) were inversely associated with the risk of EPC. Conclusion Novel associations are reported of lead, nickel and selenium toenail concentrations with pancreas cancer risk. Furthermore, the results confirm previous associations with cadmium and arsenic. These novel findings, if replicated in independent studies, would point to an important role of trace elements in pancreatic carcinogenesis.

Introduction POP biomonitoring programs are useful for exposure assessment, to analyze patterns, and to evaluate policies. However, population-representative surveys are scarce and heterogeneous. Reports on time trends in representative samples using the same methods are rare. Objectives To analyze the distribution of serum concentrations of 19 POPs in the general population of Barcelona city in 2006, and to compare it with the distribution in 2002. Methods 231 participants in the Barcelona Health Survey were interviewed face-to-face, gave blood, and underwent a physical exam. Density plots (“POP Geoffrey Rose curves”) were used to represent the full population distribution of each compound. Results Eight POPs were each detected in > 80% of the study subjects: p,p′-DDT, p,p′-DDE, PCB congeners 118, 138, 153 and 180, HCB and β-HCH. The minimum number of POPs detected in one person was 5, and 72% of the population accumulated ≥ 10 compounds. p,p′-DDE and HCB showed the highest concentrations (median = 219 and 109 ng/g lipid, respectively). Concentrations decreased by 34–56% from 2002 to 2006. The decrease was similar in women and men, and in all age groups/birth cohorts. It was larger with increasing BMI; for p,p′-DDT, HCB and β-HCH the decrease in obese individuals was 31–44 percentage points larger than in subjects with normal weight. The distribution of POP concentrations was always switched towards higher values in women than men. POP levels also differed significantly by age, body mass index, weight gain, birth place and social class, but not by parity and breastfeeding. The two younger cohorts had a higher DDT/DDE ratio than the oldest cohort. Conclusion Although human POP contamination remains common in the city of Barcelona, concentrations decreased significantly in 4 years. Our approach suggests innovative ways to conceive, analyze and present results for other monitoring programs.

Supported in part by research grants from the Government of Catalonia (2009 SGR 1350); and CIBER de Epidemiología y Salud Pública (CIBERESP), Instituto de Salud Carlos III, Government of Spain. The authors gratefully acknowledge scientific and technical assistance provided by Tomàs López, Marta Crous-Bou, Paloma Quesada, Esther Marco, Michelle Mendez, Sílvia Geeraerd and Yolanda Rovira.

Although virtually all populations worldwide are commonly exposed to numerous persistent organic pollutants (POPs) and human concentrations vary widely, only a few countries conduct nationwide surveillance programs of POP concentrations in representative samples of the general population., Departament of Health of the Government of Catalonia; ‘Red temática de investigación cooperativa de centros en Cáncer’ (C03/10); ‘Red temática de investigación cooperativa de centros en Epidemiología y salud pública’ (C03/09); and CIBER de Epidemiología, Instituto de Salud Carlos III, Ministry of Health, Government of Spain.

8 pages, 4 pages.-- PMID: 19797353 [PubMed].-- Printed version published Nov 2009., While KRAS activation is a fundamental initiating event in the aetiopathogenesis of pancreatic ductal adenocarcinoma (PDA), environmental factors influencing the occurrence and persistence of KRAS mutations remain largely unknown. The objective was to test the hypothesis that in PDA there are aetiopathogenic relationships among concentrations of some organochlorine compounds (OCs) and the mutational status of the KRAS oncogene, as well as among the latter and coffee intake. Incident cases of PDA were interviewed and had blood drawn at hospital admission (N = 103). OCs were measured by high-resolution gas chromatography with electron capture detection. Cases whose tumours harboured a KRAS mutation had higher concentrations of p,p′-dichlorodiphenyltrichloroethane (DDT), p,p′-dichlorodiphenyldichloroethene (DDE) and polychlorinated biphenyls (PCBs) 138, 153 and 180 than cases with wild-type KRAS, but differences were statistically significant only for p,p′-DDT and PCBs 138 and 153. The association between coffee intake and KRAS mutations remained significant (P-trend, Government of Catalonia (2009 SGR 1350); ‘Red temática de investigación cooperativa de centros en Cáncer’ (C03/10); ‘Red temática de investigación cooperativa de centros en Epidemiología y salud pública’ (C03/09); CIBER de Epidemiología y Salud Pública, Instituto de Salud Carlos III, Madrid, Government of Spain.

Knowledge is scant on the relationships between pathophysiologic processes common during cancer progression and changes in blood concentrations of organochlorine compounds (OCs). To analyze the influence of tumor stage, cancer symptoms, and time of blood extraction on serum concentrations of OCs in exocrine pancreatic cancer (EPC). Subjects were 144 incident cases of EPC prospectively recruited in eastern Spain. Blood was drawn and face-to-face interviews with patients were conducted during hospital admission. Information on signs and symptoms was obtained from medical records and patient interviews. OCs were analyzed by high-resolution gas chromatography with electron-capture detection. General linear models were applied to analyze log-transformed OCs corrected for total lipids. Lower concentrations of six of the seven OCs analyzed (p,p′-DDE, three polychlorinated biphenyls, hexachlorobenzene, and β-hexachlorocyclohexane) were observed in patients with cholestatic syndrome (jaundice, hypocholia, and choluria). The constitutional syndrome increased only p,p′-DDT. The lowering effect of the cholestatic syndrome was stronger than the increasing effect of the constitutional syndrome (fatigue, anorexia, and weight loss), except for p,p′-DDT. When symptoms were considered, stage had only weakly inverse relationships with OC levels. The effects of symptoms on p,p′-DDE, p,p′-DDT, and the three PCBs remained significant after adjusting by the interval from blood extraction to first symptom of EPC, and even when further adjusting by stage. Restriction or adjustment by stage and timing of blood draw may be insufficient to prevent biases associated with cancer progression. Symptoms may enable investigators to assess disease-induced changes in lipophilic exposure biomarkers.

Introduction: When studying the effects of organochlorine compounds (OCs) on human health it is common to correct serum concentrations of OC by total lipids (TL). However, the relationship between serum OCs and serum TL is far from established in many diseases, including several cancers. Our aim was to analyze the relationship between serum OC and TL in patients with pancreatic ductal adenocarcinoma (PDA), and to explore several alternatives to perform the OC lipid correction. Methods: Incident cases of PDA were interviewed and had blood drawn soon around hospital admission (n=144). Serum concentrations of OCs were analysed by high-resolution gas chromatography with electron-capture detection. Results: Most patients with high TL had moderate or low concentrations of OCs. By contrast, the variability of OC values among patients with normal TL was large. Correlations were of a similar magnitude between OC and TL and between OC and total cholesterol; while these correlations were weak (all Spearman's ρ

Background: No studies have investigated the relation between K- ras mutations and dietary factors in exocrine pancreatic cancer (EPC), and fewer than 10 studies have done so in other neoplasms. Patients and Methods: Incident cases of EPC were prospectively identified, and interviewed face-to-face during hospital admission. Food and nutrient intakes were measured with a food frequency questionnaire. Logistic regression was used to compare EPC cases (n = 107) with and without K- ras mutations (case-case study). Results: K- ras mutations were more common among daily consumers of milk and other dairy products than among non-daily consumers: the odds ratio adjusted by total energy, age, sex, smoking, alcohol and coffee consumption (ORa) was 5.1 (95% CI 1.1 to 24.5, p = 0.040). For all dairy products, including butter, the ORa for the medium and upper tertiles of intake were 5.4 and 11.6, respectively (p for trend = 0.023). The ORa for regular coffee drinkers further adjusted by dairy consumption was 4.7 (95% CI 1.1 to 20.7, p = 0.043). K- ras mutated cases reported a lower intake of vitamin E (ORa = 0.2, p for trend = 0.036), polyunsaturated fats and omega 3 fatty acids (ORa = 0.2; p for trend Conclusions: Results support the hypothesis that in EPC exposure to specific dietary components or contaminants may influence the occurrence or persistence of K- ras mutations.

Objective: Disease-induced changes in blood concentrations of lipids may bias etiologic studies. We analyzed the influence of clinical factors and timing of blood extraction on serum concentrations of cholesterol and triglycerides in exocrine pancreatic cancer (EPC). Study Design and Setting: Subjects were 144 incident cases of EPC prospectively recruited in five teaching hospitals in eastern Spain. Results: Higher concentrations of cholesterol, triglycerides, and total lipids were observed among patients with a shorter interval from first symptom of cancer to blood extraction (IES); but concentrations were lower in patients with longer IES. The relationship between cholesterol and tumor stage was ‘‘n-shaped.’’ Jaundice and other components of the cholestatic syndrome increased cholesterol and triglycerides. Invasive diagnostic tests were associated with lower cholesterol. All these factors were related to changes O50 mg/dl in cholesterol (P ! 0.05), even when adjusting by stage. Statistical models including IES, number of invasive diagnostic tests, jaundice, weight loss, and stage explained over 28% of the variation in lipid concentrations. Conclusion: Restrictionandadjustmentbystagemaybeinsufficienttopreventbiasesrelatedtodiseaseprogression.Multivariateanalyses mayallow tocontrol tosomeextenttheinfluenceof clinicalsymptoms,procedures, andtimingof bloodextractionin studiesontheetiological significance of lipids and lipophilic compounds, either risk factors or protective agents. 2008 Elsevier Inc. All rights reserved.

There are no consensus guidelines or standards for epidemiologic and '-omics' studies using blood biomarkers on how to report the timing of extraction of blood samples. However, disease-induced changes in blood concentrations of exogenous and endogenous compounds may bias studies. The aim of the present report is to describe the timing of blood collection with respect to a variety of relevant clinical events in the PANKRAS II Study, and to suggest ways to display graphically the quantitative information. Subjects were 167 incident cases of exocrine pancreatic cancer prospectively recruited in five teaching hospitals in eastern Spain. Over 80% of patients had blood extracted during the first 6 months since onset of cancer symptoms, and 82% within the first month of admission to a study hospital. Over 80% of cases had blood drawn after an ultrasound, a CT scan or an ERCP, 25% after a laparotomy, and 37% after treatment onset. All three intervals from blood extraction to diagnosis, to treatment onset and to interview had a median of 0 days, and 88% of cases had blood drawn within 2 weeks of diagnosis. Over 72% of cases had concentrations of total lipids in the medium, normal range. Results suggest ways to report intervals involving blood biomarkers and may contribute to develop consensus guidelines and standards on the collection of blood samples in epidemiologic and '-omics' research.