Person: Grandjean, Philippe
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Grandjean
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Grandjean, Philippe
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Publication Gender differences in cognitive performance and health status in the Faroese Septuagenarians cohort(Oxford University Press (OUP), 2018-07-18) Petersen, Maria Skaalum; Debes, Fróði; Grandjean, Philippe; Weihe, PálThe aim was to determine cognitive performance and health status in the Faroese Septuagenarians cohort in relation to gender differences. In this cross-sectional study of 713 Faroese septuagenarians who underwent a clinical, neurophysiological and neuropsychological examinations and questionnaire, women performed better on tests covering the memory domain, while there was no gender difference in other cognitive domains. Men suffered more frequently from cardiovascular events while women more frequently suffered from arthrosis, hypothyroidism and muscle pain. We observed a considerable heterogeneity and gender difference in some cognitive domains and health in Faroese septuagenarians.Publication Benchmark Dose Calculation from Epidemiological Data(Wiley, 2001-09) Budtz-Jørgensen, Esben; Keiding, Niels; Grandjean, PhilippeA threshold for dose-dependent toxicity is crucial for standards setting but may not be possible to specify from empirical studies. Crump (1984) instead proposed calculating the lower statistical confidence bound of the benchmark dose, which he defined as the dose that causes a small excess risk. This concept has several advantages and has been adopted by regulatory agencies for establishing safe exposure limits for toxic substances such as mercury. We have examined the validity of this method as applied to an epidemiological study of continuous response data associated with mercury exposure. For models that are linear in the parameters, we derived an approximative expression for the lower confidence bound of the benchmark dose. We find that the benchmark calculations are highly dependent on the choice of the dose-effect function and the definition of the benchmark dose. We therefore recommend that several sets of biologically relevant default settings be used to illustrate the effect on the benchmark results and to stimulate research that will guide an a priori choice of proper default settings.Publication Sperm Aneuploidy in Faroese Men with Lifetime Exposure to Dichlorodiphenyldichloroethylene (p,p´-DDE) and Polychlorinated Biphenyl (PCB) Pollutants(National Institute of Environmental Health Sciences, 2015) Perry, Melissa J.; Young, Heather A.; Grandjean, Philippe; Halling, Jónrit; Petersen, Maria Skaalum; Martenies, Sheena E.; Karimi, Parisa; Weihe, PálBackground: Although it is known that sperm aneuploidy contributes to early pregnancy losses and congenital abnormalities, the causes are unknown and environmental contaminants are suspected. Objectives: Our goal was to evaluate associations between lifetime exposure to organochlorines, specifically dichlorodiphenyldicholorethylene (p,p´-DDE) and polychlorinated biphenyls (PCBs), and sperm aneuploidy in men from the general population of the Faroe Islands, a population with a known history of organochlorine exposures. Methods: Serum and semen samples from men (n = 90) 22–44 years old who participated in Faroe Islands health studies were analyzed for p,p´-DDE and PCBs 118, 138, 153, and 180 and adjusted for total lipids. Cord blood and age-14 serum were available for a subgroup (n = 40) and were also analyzed for p,p´-DDE and PCBs. Sperm fluorescence in situ hybridization (FISH) for chromosomes X, Y, and 18 was used to determine rates of XX18, XY18, YY18, and total disomy. Multivariable adjusted Poisson models were used to estimate the relationship between organochlorine exposure and sperm disomy outcomes. Results: Adult p,p´-DDE and total PCB serum concentrations were both associated with significantly increased rates of XX18, XY18, and total disomy. Age-14 p,p´-DDE and PCB concentrations were both associated with significantly increased rates of XX, XY, and total disomy in adulthood. Associations between cord blood concentrations of p,p´-DDE and PCBs and sperm disomy in adulthood were not consistently significant. Conclusions: Organochlorine exposures measured at age 14 and in adulthood were associated with sperm disomy in this sample of high-exposure men, suggesting that the impacts of persistent pollutants on testicular maturation and function require further investigation. Citation: Perry MJ, Young HA, Grandjean P, Halling J, Petersen MS, Martenies SE, Karimi P, Weihe P. 2016. Sperm aneuploidy in Faroese men with lifetime exposure to dichlorodiphenyldichloroethylene (p,p´-DDE) and polychlorinated biphenyl (PCB) pollutants. Environ Health Perspect 124:951–956; http://dx.doi.org/10.1289/ehp.1509779Publication Toxicologic evidence of developmental neurotoxicity of environmental chemicals(Elsevier BV, 2000) Andersen, Helle Raun; Nielsen, Jesper Bo; Grandjean, PhilippeDevelopmental neurotoxicity constitutes effects occurring in the offspring primarily as a result of exposure of the mother during pregnancy and lactation. To exert their effect, these chemicals or their metabolites must pass the placenta and/or the blood–brain barrier. In experimental animals, exposure to neurotoxic chemicals during critical periods of brain development has induced permanent functional disturbances in the CNS. Although available data suggest that proper animal models exist, only few chemicals have been tested. Neurotoxicity testing is not required by national authorities for classification of chemicals. Epidemiological evidence is very limited, but severe irreversible effects have been observed in humans following in utero exposures to a few known developmental neurotoxicants. The large number of chemicals with a potential for developmental neurotoxicity in humans stresses the importance of generating basic kinetic data on these chemicals based on relevant experimental models. First of all, data are needed on their ability to pass the placenta and the developing blood–brain barrier, to accumulate, and to be metabolized in the placenta and/or the fetus. These kinetic data will be essential in establishing a scientifically based hazard evaluation and risk assessment.Publication Benchmark dose calculations of methylmercury-associated neurobehavioural deficits(Elsevier BV, 2000) Budtz-Jørgensen, Esben; Grandjean, Philippe; Keiding, Niels; White, Roberta; Weihe, PalPrenatal methylmercury exposure is associated with neuropsychological deficits in Faroese children at age 7 years. Lower confidence bounds of benchmark doses (BMDLs) have now been calculated. With the cord-blood mercury concentration as the dose parameter, a logarithmic dose-response model tended to show a better fit than a linear dose model for the attention, language and verbal memory tests. The lowest BMDLs averaged ≈5 μg/l cord blood, which corresponds to a maternal hair concentration of ≈1 μg/g. However, most BMDLs for hair mercury concentrations were higher. Thus, the results of the benchmark calculations depend on the assumed dose-response model.Publication Calculation of the disease burden associated with environmental chemical exposures: application of toxicological information in health economic estimation(BioMed Central, 2017) Grandjean, Philippe; Bellanger, MartineCalculation of costs and the Burden of Disease (BoD) is useful in developing resource allocation and prioritization strategies in public and environmental health. While useful, the Disability-Adjusted Life Year (DALY) metric disregards subclinical dysfunctions, adheres to stringent causal criteria, and is hampered by gaps in environmental exposure data, especially from industrializing countries. For these reasons, a recently calculated environmental BoD of 5.18% of the total DALYs is likely underestimated. We combined and extended cost calculations for exposures to environmental chemicals, including neurotoxicants, air pollution, and endocrine disrupting chemicals, where sufficient data were available to determine dose-dependent adverse effects. Environmental exposure information allowed cost estimates for the U.S. and the EU, for OECD countries, though less comprehensive for industrializing countries. As a complement to these health economic estimations, we used attributable risk valuations from expert elicitations to as a third approach to assessing the environmental BoD. For comparison of the different estimates, we used country-specific monetary values of each DALY. The main limitation of DALY calculations is that they are available for few environmental chemicals and primarily based on mortality and impact and duration of clinical morbidity, while less serious conditions are mostly disregarded. Our economic estimates based on available exposure information and dose-response data on environmental risk factors need to be seen in conjunction with other assessments of the total cost for these environmental risk factors, as our estimate overlaps only slightly with the previously estimated environmental DALY costs and crude calculations relying on attributable risks for environmental risk factors. The three approaches complement one another and suggest that environmental chemical exposures contribute costs that may exceed 10% of the global domestic product and that current DALY calculations substantially underestimate the economic costs associated with preventable environmental risk factors. By including toxicological and epidemiological information and data on exposure distributions, more representative results can be obtained from utilizing health economic analyses of the adverse effects associated with environmental chemicals. Electronic supplementary material The online version of this article (10.1186/s12940-017-0340-3) contains supplementary material, which is available to authorized users.Publication Secondary sex ratio in relation to exposures to polychlorinated biphenyls, dichlorodiphenyl dichloroethylene and methylmercury(Taylor & Francis, 2017) Timmermann, Clara Amalie Gade; Choi, Anna L.; Petersen, Maria Skaalum; Nielsen, Flemming; Budtz-Jørgensen, Esben; Weihe, Pál; Grandjean, PhilippeABSTRACT This study was undertaken to assess the potential impact of maternal exposures to polychlorinated biphenyl (PCB), dichlorodiphenyl dichloroethylene (DDE) and methylmercury on the secondary sex ratios (the ratio of male to female live births) over a span of 23 years. The study includes prospective data from three Faroese birth cohorts, with a total of 2,152 healthy mother–child dyads recruited between 1986 and 2009. The Faroe Islands is a subarctic fishing community, where pilot whale meat and blubber are part of the traditional marine diet. Exposures were measured in maternal hair, serum or umbilical cord blood. Confounder adjusted logistic regression models were used to assess the associations between maternal exposures and the secondary sex ratio. A doubling in ΣPCB, p,p’-DDE and mercury concentrations were associated with increased odds by 8% (95% CI = 0–16%), 7% (95% CI = 0–14%) and 9% (95% CI = 2–17%), respectively, of giving birth to a boy. In conclusion, maternal exposure to ΣPCB, DDE and methylmercury was associated with a slightly increased secondary sex ratio. The impact of paternal exposures could not be taken into account and deserves attention.Publication Sensitivity of continuous performance test (CPT) at age 14years to developmental methylmercury exposure(Elsevier BV, 2010) Julvez, Jordi; Debes, Frodi; Weihe, Pal; Choi, Anna; Grandjean, PhilippeHit Reaction Time latencies (HRT) in the Continuous Performance Test (CPT) measure the speed of visual information processing. The latencies may involve different neuropsychological functions depending on the time from test initiation, i.e., first orientation, learning and habituation, then cognitive processing and focused attention, and finally sustained attention as the dominant demand. Prenatal methylmercury exposure is associated with increased reaction time (RT) latencies. We therefore examined the association of methylmercury exposure with the average HRT at age 14 years at three different time intervals after test initiation. A total of 878 adolescents (87% of birth cohort members) completed the CPT. The RT latencies were recorded for 10 minutes, with visual targets presented at 1000 ms intervals. After confounder adjustment, regression coefficients showed that CPT-RT outcomes differed in their associations with exposure biomarkers of prenatal methylmercury exposure: During the first two minutes, the average HRT was weakly associated with methylmercury (beta (SE) for a ten-fold increase in exposure, (3.41 (2.06)), was strongly for the 3-to-6 minute interval (6.10 (2.18)), and the strongest during 7–10 minutes after test initiation (7.64 (2.39)). This pattern was unchanged when simple reaction time and finger tapping speed were included in the models as covariates. Postnatal methylmercury exposures did not affect the outcomes. Thus, these findings suggest that sustained attention as a neuropsychological domain is particularly vulnerable to developmental methylmercury exposure, indicating probable underlying dysfunction of the frontal lobes. When using CPT data as a possible measure of neurotoxicity, test results should therefore be analyzed in regard to time from test initiation and not as overall average reaction times.Publication Psychological dysfunctions in lead-exposed workers: Relation to biological parameters of exposure.(Nordic Association of Occupational Safety and Health, 1978) Grandjean, Philippe; Arnvig, E; Beckmann, JInsidious neurotoxic effects of lead have been studied in a population of 42 lead-exposed workers and a reference group of 22 comparable workers with no lead exposure. The age of the individuals ranged from 18 to 50 years. The complete Wechler Adult Intelligence Scale, as well as psychomotor and memory tests, was included in the test battery. The exposure was assessed by means of the lead concentration in blood and hair and the ratio between zinc protoporphyrin and hemoglobin in the blood. Significant differences were found between the two groups of workers, especially concerning long-term memory, verbal and visuospatial abstraction, and psychomotor speed. Decreased performance in these tests was in most cases associated with indices of increased lead exposure, not only in the total population studied, but also within the lead-exposed group alone. Blood lead and zinc protoporphyrin appeared to correlate better with the intellectual impairment than did hair lead, and thus these analyses are probably better predictors for neurotoxic effects of lead. Age and exposure time were not found to be significant confounding factors in this study.Publication Association between mercury concentrations in blood and hair in methylmercury-exposed subjects at different ages(Elsevier BV, 2004) Budtz-Jørgensen, Esben; Jørgensen, Poul J; Grandjean, Philippe; Weihe, Pal; Keiding, NielsMercury concentrations were measured in paired hair and blood samples from a cohort of about 1000 children examined at birth and at 7 and 14 years of age. The ratio between concentrations in maternal hair (in μg/g) and in cord blood (μg/L) was approximately 200, but samples from the children at age 14 years showed a ratio of about 250. These findings are in accordance with previous data from smaller studies. However, an even higher ratio of about 360 was seen at 7 years of age, suggesting that hair strands at this age retain more mercury. The 95th percentile of the hair-to-blood ratio was between five-fold and nine-fold greater than the 5th percentile. The results were examined in structural equation models to estimate the total imprecision of the individual biomarker results and the possibility that the ratio may not be constant. The hair-to-blood ratio was found to increase at lower mercury concentrations, a tendency that could not be explained by potential confounders, such as alcohol intake or number of amalgam fillings. The total imprecision (coefficient of variation) for the blood determinations averaged about 30%, thereby substantially exceeding normal laboratory imprecision. Yet hair-mercury results had an even greater imprecision, which suggested that preanalytical factors, such as variable sample characteristics, impacted the results. These findings are in accordance with other evidence that the cord blood concentration is a better predictor of neurobehavioral toxicity than is the maternal hair concentration. Although practical for field studies and monitoring purposes, hair-mercury concentration results, therefore, need to be calibrated and interpreted in regard to each specific study setting.