PubMed Health⌕ Search

Biomedical subjects

P Grandjean

Publications and source records attributed to P Grandjean.

At least 19 recordsLinked to original sources

Developmental neurotoxicity of industrial chemicals.

Neurodevelopmental disorders such as autism, attention deficit disorder, mental retardation, and cerebral palsy are common, costly, and can cause lifelong disability. Their causes are mostly unknown. A few industrial chemicals (eg, lead, methylmercury, polychlorinated biphenyls [PCBs], arsenic, and toluene) are recognised causes of neurodevelopmental disorders and subclinical brain dysfunction. Exposure to these chemicals during early fetal development can cause brain injury at doses much lower than those affecting adult brain function. Recognition of these risks has led to evidence-based programmes of prevention, such as elimination of lead additives in petrol. Although these prevention campaigns are highly successful, most were initiated only after substantial delays. Another 200 chemicals are known to cause clinical neurotoxic effects in adults. Despite an absence of systematic testing, many additional chemicals have been shown to be neurotoxic in laboratory models. The toxic effects of such chemicals in the developing human brain are not known and they are not regulated to protect children. The two main impediments to prevention of neurodevelopmental deficits of chemical origin are the great gaps in testing chemicals for developmental neurotoxicity and the high level of proof required for regulation. New, precautionary approaches that recognise the unique vulnerability of the developing brain are needed for testing and control of chemicals.

Adolescent↗

Trends in mercury in hair of Greenlandic polar bears (Ursus maritimus) during 1892-2001.

Mercury concentrations in hair from 397 Greenland polar bears (Ursusmaritimus) sampled between 1892 and 2001 were analyzed for temporal trends. In East Greenland the concentrations showed a significant (p < 0.0001, n = 27) increase of 3.1%/year in the period 1892-1973. In Northwest Greenland, a similar (p < 0.0001, n = 69) increase of 2.1%/year was found, which continued until 1991, when the most recent samples were obtained. In East Greenland, a significant (p = 0.009, n = 322) decrease of 0.8%/year was observed after 1973. Two Northwest Greenland samples from 1300 A.D. had a mean value of 0.52 mg/kg of dry weight, which can be considered as a baseline level. The Hg concentration during 1985-1991 from Northwest Greenland (mean value of 7.45 mg/kg of dry weight) was more than 14-fold higher than the assumed baseline level from 1300 A.D. from the same region (i.e., about 93% anthropogenic). Although a decrease was found in East Greenland after 1973, the concentration is still ca. 11-fold higher than the baseline level (i.e., about 90% anthropogenic).

Animals↗

Organochlorine exposures influence on breast cancer risk and survival according to estrogen receptor status: a Danish cohort-nested case-control study.

BACKGROUND: The relationship between breast cancer and organochlorine exposure is controversial and complex. As estrogen receptor positive and negative breast cancer may represent different entities of the disease, this study was undertaken to evaluate organochlorines influence on breast cancer risk and survival according to receptor status. METHODS: The background material stems from the Copenhagen City Heart Study (Denmark 1976-78). The breast cancer risk was investigated in a cohort nested case-control design including 161 cases and twice as many breast cancer free controls. The cases served as a cohort in the survival analysis. Serum organochlorine concentrations were determined by gaschromotography. RESULTS: The observed increased breast cancer risk associated with exposure to dieldrin derived from women who developed an estrogen receptor negative (ERN) tumor (Odds ratio [OR] I vs. IV quartile, 7.6, 95% confidence interval [95% CI] 1.4-46.1, p-value for linear trend 0.01). Tumors in women with the highest dieldrin serum level were larger and more often spread at the time of diagnosis than ERP tumors. The risk of dying was for the remaining evaluated compounds higher among patients with ERP breast cancer when compared to those with ERN. In the highest quartile of polychlorinated biphenyls (SigmaPCB) it was more than 2-fold increased (Relative risk [RR] I vs. IV quartile, 2.5, 95% CI 1.1-5.7), but no dose-response relation was apparent. CONCLUSION: The results do not suggest that exposure to potential estrogenic organochlorines leads to development of an ERP breast cancer. A possible adverse effect on prognosis of hormone-responsive breast cancers needs to be clarified.

Adult↗

Birthweight in a fishing community: significance of essential fatty acids and marine food contaminants.

BACKGROUND: Marine food provides essential fatty acids that are important during pregnancy, but the benefits may be limited at high intakes and by seafood contaminants. METHODS: In the fishing community of the Faroe Islands, 182 pregnant women with spontaneous singleton births were consecutively recruited for a cohort in 1994- 1995. Concentrations of fatty acids and seafood contaminants in blood samples were analysed as predictors of gestational length and birthweight. RESULTS: Serum concentrations of eicosapentaenoic acid (EPA) increased with maternal marine food intake, while the tendency was less clear for docosahexaenoic acid (DHA). An increase in the relative concentration of DHA in cord serum phospholipids by 1% was associated with an increased duration of gestation by 1.5 days (95% CI : 0.7-2.2). However, birthweight adjusted for gestational length decreased by 246 g (95% CI : 16-476) for each increase by 1% of the EPA concentration in cord serum. Concentrations of the seafood pollutants mercury and polychlorinated biphenyls (PCB) were associated with fatty acids levels, but the contaminants did not appear to affect any of the outcome parameters. CONCLUSION: An increased intake of marine fats appears to prolong the duration of gestation, but birthweight adjusted for gestational age may decrease at high intake levels. This effect does not seem to be due to increased exposures to seafood contaminants.

Birth Weight↗

Benchmark dose calculation from epidemiological data.

A 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.

Animals↗

Selection bias in determining the age dependence of waiting time to pregnancy.

Many studies have found decreased fecundability, that is, the ability to conceive in a menstrual cycle, with increasing female age. To evaluate the effect of maternal age on waiting time to pregnancy, the authors reviewed hospital charts of all pregnant women attending prophylactic antenatal care at Odense University Hospital, Denmark, during 1972-1987. Only the first pregnancy of each woman and only planned pregnancies were included (n = 14,754). The fecundability odds ratio (FR) was calculated as the odds of a conception in a menstrual cycle among the older women divided by the odds among women aged 15-24 years. The FR for women aged 25-29 years was 1.12 (95% confidence interval (CI): 1.04, 1.20), for women aged 30-34 years it was 1.15 (95% CI: 1.01, 1.30), and for women above 34 years the FR was 2.44 (95% CI: 1.84, 3.22) after adjustment for confounders. The increased fecundability with age is contrary to previous studies and may be explained by selection bias, as sterile women were not included. In addition, some very fertile young women who became pregnant by accident before efficient birth control methods were available and therefore were excluded from time to pregnancy studies may now use oral contraceptives until they plan a pregnancy later in life and are included.

Adolescent↗

Toxicologic evidence of developmental neurotoxicity of environmental chemicals.

Developmental 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.

Animals↗

Linac radiosurgery for cerebral arteriovenous malformations: results in 169 patients.

PURPOSE: To present the SALT group results using Linac radiosurgery (RS) for AVM in 169 evaluable patients treated from January 1990 thru December 1993. METHODS AND MATERIALS: Median age was 33 years (range 6-68 years). Irradiation was the only treatment in 55% patients. Other treatment modalities had been used prior to RS in 45%: one or more embolizations in 36%, surgery in 6%, and embolization and surgery in 3% patients. Nidus were supratentorial in 94% patients, infratentorial in 6% patients. Circular 15 MV x-ray minibeams (6-20 mm) were delivered in coronal arcs by a GE-CGR Saturne 43 Linac. Patient set-up included a Betti arm-chair, a Talairach frame. Prescribed peripheral dose was 25 Gy on the 60%-70% isodose (max dose 100%). Arteriographic results were reassessed in December 1997 at 48 to 96 months follow-up. RESULTS: The overall obliteration rate (OR) was 64% (108/169). AVM volumes ranged from 280 to 19,920 mm(3), median 2460 mm(3). OR was 70% for AVM </= 4200 mm(3) 4200 mm(3) (p 25 mm (p = 0.04). OR was 71%, in the absence of embolization, vs. 54% for previously embolized nidus (p = 0.03). OR was 71% for monocentric RS vs. 54% for multi-isocenters (p 28 Gy vs. 55% for values </= 28 Gy (p 79% vs. 57% for lower values (p 17 Gy, vs. 59% for mLd </= 16 Gy (p 40%, vs. 54% for mLi </= 40% (p 85% vs. 60% for CR </= 84% (NS). For patients treated according to our protocol, i.e., 24-26 Gy on the 60%-70% isodoses, OR was higher (68%) than for other patients (47%) (p = 0.02). After multivariate analysis, absence of previous embolization and mono isocentric-irradiation were independent factors predicting obliteration. Complications were: recurrent hemorrhage, 4 patients (1 patient died); brain necrosis on MRI, 2 patients; subsequent epilepsy, 4 patients; other subsequent neurologic deficits, 3 patients. CONCLUSION: Overall OR was 64% (48-96 months follow-up). After monovariate analysis higher ORs were associated with smaller volumes </= 4200 mm(3), smaller nidus size </= 25 mm, absence of prior embolization, monoisocentric RS, higher values for mean and minimum lesion doses and compliance to our protocol. Higher values for the peripheral dose and isodose tended to give better results. Multivariate analysis showed that the absence of prior embolization and monoisocentric irradiation were independent factors predicting successful irradiation.

Adolescent↗

Benchmark dose calculations of methylmercury-associated neurobehavioural deficits.

Prenatal 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 approximately 5 microgram/l cord blood, which corresponds to a maternal hair concentration of approximately 1 microgram/g. However, most BMDLs for hair mercury concentrations were higher. Thus, the results of the benchmark calculations depend on the assumed dose-response model.

Biomarkers↗

Organochlorine exposure and breast cancer survival.

Recent research suggests that exposure to organochlorines, such as dieldrin that possess estrogenic properties, may increase the risk of breast cancer by promoting growth of malignant cells. Whether this potential also affects malignant cells not eradicated by treatment, and thereby survival, is unknown. To evaluate this blood samples from female participants in the Copenhagen City Heart Study, Denmark, were analyzed for organochlorines. A total of 195 breast cancer cases, who each provided two blood samples that were taken in 1976-78 and 1981-83, respectively, were included in the survival analysis. Dieldrin had a significant adverse effect on overall survival and breast cancer specific survival (RR, 2.78, 95% CI, 1. 38-5.59, P trend < 0.01; RR, 2.61, 95% CI, 0.97-7.01, P trend < 0. 01). This association was strengthened when exposure was assessed as the average serum concentration of the two measurements. These findings suggest that past exposure to estrogenic organochlorines such as dieldrin may not only affect the risk of developing breast cancer but also the survival.

Adult↗

[Organochlorine compounds and breast cancer--is there a connection between environmental pollution and breast cancer?].

Some organochlorine compounds may have weak oestrogenic effects and are therefore suspected of increasing the risk of breast cancer. The risk of breast cancer was assessed prospectively in relation to the serum concentration of several organochlorines. In all 240 women, who developed breast cancer between 1976 and 1993 were together with 477 breast cancer-free controls enrolled in a cohort-nested case-control study. The serum dieldrin concentration was associated with a significantly increased dose-related risk of breast cancer (Odds Ratio 2.05; 95% confidence interval 1.17-3.57; p for trend 0.01). There was no overall association between risk of breast cancer and DDT or polychlorinated biphenyls. The results support the hypothesis that exposure to oestrogenic organochlorines may increase the risk of breast cancer.

Breast Neoplasms↗

Repeated measurements of organochlorine exposure and breast cancer risk (Denmark).

OBJECTIVE: To prospectively evaluate if repeated measurements of organochlorine exposure provide a more precise measure of breast cancer risk. METHODS: In the Copenhagen City Heart Study (CCHS) participants donated blood twice, in 1976-1978 and 1981 1983. Information on breast cancer risk factors was obtained through standardized questionnaires. A cohort nested case-control study of 155 cases and 274 matched breast cancer-free controls who had participated in both CCHS examinations was conducted. The average serum organochlorine concentration over the course of the two examinations was used, testing a possible association between organochlorine exposure and breast cancer risk. RESULTS: A high serum concentration of p,p'-DDT over the course of the two examinations was associated with a more than three-fold significantly increased risk of breast cancer, and a dose-response relationship was apparent. Furthermore, the risk of breast cancer increased with increasing serum concentrations of PCB congener 118 and 138 and the total amount of DDT isomers (sigmaDDT), but the trends were not significant. CONCLUSION: This study provides new evidence of the adverse effect of some organochlorines on breast cancer risk. Furthermore, repeated assessment of exposure during a relevant time period may provide a more precise risk estimate than a single measurement.

Adult↗

Maternal seafood diet, methylmercury exposure, and neonatal neurologic function.

OBJECTIVE: To determine whether neonatal neurologic function is adversely affected by seafood contaminants from maternal diet during pregnancy. STUDY DESIGN: One hundred eighty-two singleton term births were evaluated in the Faeroe Islands, where marine food includes pilot whale. Maternal serum, hair, and milk and umbilical cord blood were analyzed for contaminants. Levels of essential fatty acids, selenium, and thyroid hormones were determined in cord blood. Each infant's neurologic optimality score was determined at 2 weeks of age adjusted for gestational age, and predictors were assessed by regression analysis. RESULTS: Exposures to methylmercury and polychlorinated biphenyls were increased in relation to maternal seafood intake, as were omega3 fatty acid concentrations in cord serum. Thyroid function was normal. After adjustment for confounders, a 10-fold increase of the cord-blood mercury concentration was associated with a decreased neurologic optimality score of 2.0 (P =. 03). This effect corresponds to a decrease in gestational age of about 3 weeks. Other indicators of the seafood diet had no effect on this outcome. CONCLUSIONS: Prenatal exposure to methylmercury from contaminated seafood was associated with an increased risk of neurodevelopmental deficit. Thus in this North Atlantic population, methylmercury constituted an important neurologic risk factor, although effects of other seafood components were not detectable.

Adult↗