Esben Budtz-Jørgensen

Neurobehavioral deficits associated with PCB in 7-year-old children prenatally exposed to seafood neurotoxicants.

Prenatal exposure to polychlorinated biphenyls (PCBs) was examined by analysis of cord tissue from 435 children from a Faroese birth cohort. Analysis of 50 paired cord blood samples showed excellent correlation with the cord tissue concentration (r=.90). Among 17 neuropsychological outcomes determined at age 7 years, the cord PCB concentration was associated with deficits on the Boston Naming Test (without cues, two-tailed P=.09 not adjusted for mercury; with cues, P=.03), the Continuous Performance Test reaction time (P=.03), and, possibly, on long-term recall on the California Verbal Learning Test (P=.15). The association between cord PCB and cord-blood mercury (r=.42) suggested possible confounding. While no PCB effects were apparent in children with low mercury exposure, PCB-associated deficits within the highest tertile of mercury exposure indicated a possible interaction between the two neurotoxicants. PCB-associated increased thresholds were seen at two of eight frequencies on audiometry, but only on the left side, and no deficits occurred on evoked potentials or contrast sensitivity. The limited PCB-related neurotoxicity in this cohort appears to be affected by concomitant methylmercury exposure.

Serum Vaccine Antibody Concentrations in Children Exposed to Perfluorinated Compounds

CONTEXT Perfluorinated compounds (PFCs) have emerged as important food contaminants. They cause immune suppression in a rodent model at serum concentrations similar to those occurring in the US population, but adverse health effects of PFC exposure are poorly understood. OBJECTIVE To determine whether PFC exposure is associated with antibody response to childhood vaccinations. DESIGN, SETTING, AND PARTICIPANTS Prospective study of a birth cohort from the National Hospital in the Faroe Islands. A total of 656 consecutive singleton births were recruited during 1997-2000, [corrected] and 587 participated in follow-up through 2008. MAIN OUTCOME MEASURES Serum antibody concentrations against tetanus and diphtheria toxoids at ages 5 and 7 years. RESULTS Similar to results of prior studies in the United States, the PFCs with the highest serum concentrations were perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA). Among PFCs in maternal pregnancy serum, PFOS showed the strongest negative correlations with antibody concentrations at age 5 years, for which a 2-fold greater concentration of exposure was associated with a difference of -39% (95% CI, -55% to -17%) in the diphtheria antibody concentration. PFCs in the childs serum at age 5 years showed uniformly negative associations with antibody levels, especially at age 7 years, except that the tetanus antibody level following PFOS exposure was not statistically significant. In a structural equation model, a 2-fold greater concentration of major PFCs in child serum was associated with a difference of -49% (95% CI, -67% to -23%) in the overall antibody concentration. A 2-fold increase in PFOS and PFOA concentrations at age 5 years was associated with odds ratios between 2.38 (95% CI, 0.89 to 6.35) and 4.20 (95% CI, 1.54 to 11.44) for falling below a clinically protective level of 0.1 IU/mL for tetanus and diphtheria antibodies at age 7 years. CONCLUSION Elevated exposures to PFCs were associated with reduced humoral immune response to routine childhood immunizations in children aged 5 and 7 years.

Preventive Effect of Eccentric Training on Acute Hamstring Injuries in Men’s Soccer: A Cluster-Randomized Controlled Trial

Background: The incidence of acute hamstring injuries is high in several sports, including the different forms of football. Purpose: The authors investigated the preventive effect of eccentric strengthening of the hamstring muscles using the Nordic hamstring exercise compared with no additional hamstring exercise on the rate of acute hamstring injuries in male soccer players. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: Fifty Danish male professional and amateur soccer teams (942 players) were allocated to an intervention group (461 players) or a control group (481 players). Players in the intervention group conducted a 10-week progressive eccentric training program followed by a weekly seasonal program, whereas players in the control group followed their usual training program. The main outcome measures were numbers of overall, new, and recurrent acute hamstring injuries during 1 full soccer season. Results: Fifty-two acute hamstring injuries in the control group compared with 15 injuries in the intervention group were registered. Comparing intervention versus the control group, overall acute hamstring injury rates per 100 player seasons were 3.8 versus 13.1 (adjusted rate ratio [RR], 0.293; 95% confidence interval [CI], 0.150-0.572; P < .001). New injury rates per 100 player seasons were 3.1 versus 8.1 (RR, 0.410; 95% CI, 0.180-0.933; P = .034), whereas recurrent injury rates per 100 player seasons were 7.1 versus 45.8 (RR, 0.137; 95% CI, 0.037-0.509; P = .003). Number needed to treat [NNT] to prevent 1 acute hamstring injury (new or recurrent) is 13 (95% CI, 9-23) players. The NNT to prevent 1 new injury is 25 (95% CI, 15-72) players, and NNT to prevent 1 recurrent injury is 3 (95% CI, 2-6) players. Conclusion: In male professional and amateur soccer players, additional eccentric hamstring exercise decreased the rate of overall, new, and recurrent acute hamstring injuries.

Prenatal Methylmercury Exposure as a Cardiovascular Risk Factor at Seven Years of Age

Blood pressure in childhood is an important determinant of hypertension risk later in life, and methylmercury exposure is a potential environmental risk factor. A birth cohort of 1,000 children from the Faroe Islands was examined for prenatal exposure to methylmercury, and at age 7 years, blood pressure, heart rate, and heart rate variability were determined. After adjustment for body weight, diastolic and systolic blood pressure increased by 13.9 mmHg [95% confidence limits (CL) = 7.4, 20.4] and 14.6 mmHg (95% CL = 8.3, 20.8), respectively, when cord blood mercury concentrations increased from 1 to 10 microg/liter cord blood. Above this level, which corresponds to a current exposure limit, no further increase was seen. Birth weight acted as a modifier, with the mercury effect being stronger in children with lower birth weights. In boys, heart rate variability decreased with increasing mercury exposures, particularly from 1 to 10 microg/liter cord blood, at which the variability was reduced by 47% (95% CL = 14%, 68%). These findings suggest that prenatal exposure to methylmercury may affect the development of cardiovascular homeostasis.

Separation of Risks and Benefits of Seafood Intake

Background Fish and seafood provide important nutrients but may also contain toxic contaminants, such as methylmercury. Advisories against pollutants may therefore conflict with dietary recommendations. In resolving this conundrum, most epidemiologic studies provide little guidance because they address either nutrient benefits or mercury toxicity, not both. Objectives Impact on the same health outcomes by two exposures originating from the same food source provides a classical example of confounding. To explore the extent of this bias, we applied structural equation modeling to data from a prospective study of developmental methylmercury neurotoxicity in the Faroe Islands. Results Adjustment for the benefits conferred by maternal fish intake during pregnancy resulted in an increased effect of the prenatal methylmercury exposure, as compared with the unadjusted results. The dietary questionnaire response is likely to be an imprecise proxy for the transfer of seafood nutrients to the fetus, and this imprecision may bias the confounder-adjusted mercury effect estimate. We explored the magnitude of this bias in sensitivity analysis assuming a range of error variances. At realistic imprecision levels, mercury-associated deficits increased by up to 2-fold when compared with the unadjusted effects. Conclusions These results suggest that uncontrolled confounding from a beneficial parameter, and imprecision of this confounder, may cause substantial underestimation of the effects of a toxic exposure. The adverse effects of methylmercury exposure from fish and seafood are therefore likely to be underestimated by unadjusted results from observational studies, and the extent of this bias will be study dependent.

Methylmercury exposure and adverse cardiovascular effects in Faroese whaling men.

Background Methylmercury (MeHg), a worldwide contaminant found in fish and seafood, has been linked to an increased risk of cardiovascular mortality. Objective We examined 42 Faroese whaling men (30–70 years of age) to assess possible adverse effects within a wide range of MeHg exposures from consumption of pilot whale meat. Methods We assessed exposure levels from mercury analysis of toenails and whole blood (obtained at the time of clinical examination), and a hair sample collected 7 years previously. Outcome measures included heart rate variability (HRV), blood pressure (BP), common carotid intima-media thickness (IMT), and brainstem auditory evoked potentials (BAEP). We carried out multiple regression and structural equation model (SEM) analyses to determine the confounder-adjusted effect of mercury exposure. Taking into account correlations among related measures, we categorized exposure and outcomes in groups to derive latent exposure and response variables in SEMs. We used multiple regression analysis to compare the predictive validity of individual exposure biomarkers and the latent exposure variable on individual and latent outcomes. Results The toenail mercury concentrations varied widely and had a geometric mean of 2.0 μg/g; hair concentrations averaged about 3-fold higher. Mercury exposure was significantly associated with increased BP and IMT. This effect was reflected by SEMs, but mercury in toenails tended to be the best effect predictor. Conclusions The results support the notion that increased MeHg exposure promotes the development of cardiovascular disease.

Reduced Antibody Responses to Vaccinations in Children Exposed to Polychlorinated Biphenyls

Background Developmental exposure to polychlorinated biphenyls (PCBs) has been implicated as a possible cause of deficient immune function in children. This study was designed to assess whether prenatal and postnatal exposure to PCBs impacts on antibody response to childhood immunizations. Methods and Findings Two birth cohorts were formed in the Faroe Islands, where exposures vary widely, because traditional diets may include whale blubber contaminated with PCBs. Prenatal exposure was determined from maternal concentrations of PCBs in pregnancy serum and milk. Following routine childhood vaccinations against tetanus and diphtheria, 119 children were examined at 18 mo and 129 children at 7 y of age, and their serum samples were analyzed for tetanus and diphtheria toxoid antibodies and for PCBs. The antibody response to diphtheria toxoid decreased at age 18 mo by 24.4% (95% confidence interval [CI], 1.63–41.9; p = 0.04) for each doubling of the cumulative PCB exposure at the time of examination. The diphtheria response was lower at age 7 y and was not associated with the exposure. However, the tetanus toxoid antibody response was affected mainly at age 7 y, decreasing by 16.5% (95% CI, 1.51–29.3; p = 0.03) for each doubling of the prenatal exposure. Structural equation analysis showed that the early postnatal exposure was the most important predictor of a decreased vaccination response. Conclusions Increased perinatal exposure to PCBs may adversely impact on immune responses to childhood vaccinations. The clinical implications of insufficient antibody production emphasize the need for prevention of immunotoxicant exposures.

Impaired Reproductive Development in Sons of Women Occupationally Exposed to Pesticides during Pregnancy

OBJECTIVES The aim of this prospective study was to investigate whether occupational pesticide exposure during pregnancy causes adverse effects on the reproductive development in the male infants. DESIGN AND MEASUREMENTS Pregnant women employed in greenhouses in Denmark were consecutively recruited, and 113 mother-son pairs were included. The mothers were categorized as occupationally exposed (91 sons) or unexposed (22 sons) to pesticides during pregnancy. Testicular position and volume, penile length, and position of urethral opening were determined at 3 months of age using standardized techniques. Concentrations of reproductive hormones in serum from the boys were analyzed. RESULTS The prevalence of cryptorchidism at 3 months of age was 6.2% [95% confidence interval (CI), 3.0-12.4]. This prevalence was considerably higher than among Danish boys born in the Copenhagen area (1.9%; 95% CI, 1.2-3.0) examined by the same procedure. Boys of pesticide-exposed mothers showed decreased penile length, testicular volume, serum concentrations of testosterone, and inhibin B. Serum concentrations of sex hormone-binding globulin, follicle-stimulating hormone, and the luteinizing hormone:testosterone ratio were increased compared with boys of nonexposed mothers. For individual parameters, only the decreased penile length was statistically significant (p = 0.04). However, all observed effects were in the anticipated direction, and a joint multivariate test showed that this finding had a p-value of 0.012. CONCLUSIONS Our findings suggest an adverse effect of maternal occupational pesticide exposure on reproductive development in the sons despite current greenhouse safeguards and special measures to protect pregnant women.

Evoked potentials in Faroese children prenatally exposed to methylmercury.

A study of 7-year-old children from a fishing village on Madeira has suggested that latencies of evoked potentials may be delayed because of increased exposures to methylmercury during development. Data from a previously published prospective study in the Faroe Islands have therefore been reexamined. Because of changes in instrumentation, results obtained during the second year of examination were excluded. After this restriction, the results show significant mercury-associated delays of the peak III latency and the I-III interpeak latency of the auditory brainstem evoked potentials. Mercury concentrations in both maternal hair at parturition and in cord blood indicated this association, whereas no such relationship was apparent with the childs current hair-mercury concentration. Thus, in agreement with the findings from Madeira, a delay of the peak III latency of the brainstem auditory evoked potentials appears to serve as a marker of prenatal methylmercury toxicity from contaminated seafood.

Estimation of health effects of prenatal methylmercury exposure using structural equation models

BackgroundObservational studies in epidemiology always involve concerns regarding validity, especially measurement error, confounding, missing data, and other problems that may affect the study outcomes. Widely used standard statistical techniques, such as multiple regression analysis, may to some extent adjust for these shortcomings. However, structural equations may incorporate most of these considerations, thereby providing overall adjusted estimations of associations. This approach was used in a large epidemiological data set from a prospective study of developmental methyl-mercury toxicity.ResultsStructural equation models were developed for assessment of the association between biomarkers of prenatal mercury exposure and neuropsychological test scores in 7 year old children. Eleven neurobehavioral outcomes were grouped into motor function and verbally mediated function. Adjustment for local dependence and item bias was necessary for a satisfactory fit of the model, but had little impact on the estimated mercury effects. The mercury effect on the two latent neurobehavioral functions was similar to the strongest effects seen for individual test scores of motor function and verbal skills. Adjustment for contaminant exposure to poly chlorinated biphenyls (PCBs) changed the estimates only marginally, but the mercury effect could be reduced to non-significance by assuming a large measurement error for the PCB biomarker.ConclusionsThe structural equation analysis allows correction for measurement error in exposure variables, incorporation of multiple outcomes and incomplete cases. This approach therefore deserves to be applied more frequently in the analysis of complex epidemiological data sets.