The Krümmel (Germany) Childhood Leukaemia Cluster: a review and update.

The debate surrounding possible adverse health effects from the civil use of nuclear power under normal operating conditions has been on-going since its introduction. It was particularly intensified by the detection of three leukaemia clusters near nuclear installations, i.e. near the reprocessing plants in Sellafield and Dounreay, UK, and near the Krümmel nuclear power plant, Germany, the last of which commenced between 1990 and 1991 and was first described in 1992; it continued until 2003, and an elevated risk up to 2005 has been reported in the literature. A number of expert commissions and working groups were set up by the governments of the German federal states of Lower Saxony and Schleswig-Holstein to investigate the possible causes of the cluster. An overview of the many risk factors that were investigated as a possible explanation of the Krümmel cluster is given here, focussing on radiation, but also including other risk factors. Further, results from related epidemiological and cytogenetic studies are described. In summary, the cause of the occurrence of the Krümmel cluster has to be considered as unknown. Further research on the causes of childhood leukaemia is needed, focussing on epigenetics and on gene-environment interaction. An update of the leukaemia incidence around the Krümmel site shows that the incidence rates are now comparable to the average rate in Germany.

Identification of germline susceptibility loci in ETV6-RUNX1-rearranged childhood acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is a malignant disease of the white blood cells. The etiology of ALL is believed to be multifactorial and likely to involve an interplay of environmental and genetic variables. We performed a genome-wide association study of 355 750 single-nucleotide polymorphisms (SNPs) in 474 controls and 419 childhood ALL cases characterized by a t(12;21)(p13;q22) - the most common chromosomal translocation observed in childhood ALL - which leads to an ETV6-RUNX1 gene fusion. The eight most strongly associated SNPs were followed-up in 951 ETV6-RUNX1-positive cases and 3061 controls from Germany/Austria and Italy, respectively. We identified a novel, genome-wide significant risk locus at 3q28 (TP63, rs17505102, P(CMH)=8.94 × 10(-9), OR=0.65). The separate analysis of the combined German/Austrian sample only, revealed additional genome-wide significant associations at 11q11 (OR8U8, rs1945213, P=9.14 × 10(-11), OR=0.69) and 8p21.3 (near INTS10, rs920590, P=6.12 × 10(-9), OR=1.36). These associations and another association at 11p11.2 (PTPRJ, rs3942852, P=4.95 × 10(-7), OR=0.72) remained significant in the German/Austrian replication panel after correction for multiple testing. Our findings demonstrate that germline genetic variation can specifically contribute to the risk of ETV6-RUNX1-positive childhood ALL. The identification of TP63 and PTPRJ as susceptibility genes emphasize the role of the TP53 gene family and the importance of proteins regulating cellular processes in connection with tumorigenesis.

Environmental exposure to polychlorinated biphenyls and quality of the home environment: effects on psychodevelopment in early childhood.

BACKGROUND: There is uncertainty whether environmental levels of exposure to polychlorinated biphenyls (PCBs) adversely affect mental and motor development in early childhood. We aimed to establish whether such an effect is of only prenatal or additional postnatal origin, and if a favourable home environment can counteract this effect. METHODS: Between 1993 and 1995 we recruited 171 healthy mother-infant pairs and prospectively measured psychodevelopment in newborn infants aged 7, 18, 30, and 42 months. We estimated prenatal and perinatal PCB exposure of newborn babies in cord blood and maternal milk. At 42 months we measured postnatal PCB concentrations in serum. At 18 months the quality of the home environment was assessed using the Home Observation for Measurement of the Environment scale. Mental and psychomotor development of the children were assessed using the Bayley Scales of Infant Development until 30 months and the Kaufman Assessment Battery for Children at 42 months. FINDINGS: Negative associations between milk PCB and mental/motor development were reported at all ages, becoming significant from 30 months onwards. Over 30 months, for a PCB increase from 173 (5th percentile) to 679 ng/g lipids in milk (95th percentile) there was a decrease of 8.3 points (95% CI -16.5 to 0.0) in the Bayley Scales of Infant Development mental scores, and a 9.1 point decrease (95% CI -17.2 to -1.02) in the Bayley Scales of Infant Development motor scores. There was also a negative effect of postnatal PCB exposure via breastfeeding at 42 months. Home environment had a positive effect from 30 months onwards (Bayley Scales of Infant Development mental score increase of 9.4 points [95% CI 2.2-16.7]). INTERPRETATION: Prenatal PCB exposure at current European background levels inhibits, and a favourable home environment supports, mental and motor development until 42 months of age. PCB exposure also has an effect postnatally.

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.

Dietary intake of lead, cadmium, copper and zinc by children from the German North Sea island Amrum.

The dietary intake of metals was studied in seven male and seven female children at the age of 1.5 to 5.3 years living in a remote area of Germany, the North Sea island Amrum. The dietary intake of lead and cadmium was measured by a seven-day-duplicate study using atomic absorption spectrometry. The dietary intake of copper and zinc were calculated from food diaries. The median lead and cadmium intakes were 2.1 micrograms/(kgbw x week) [range: 0.63-5.1 micrograms/(kgbw x week)] and 2.7 micrograms/(kgbw x week) [range: 1.7-4.4 micrograms/(kgbw x week)]. The median daily intake of copper and zinc were 1.1 mg/d (range: 0.54-2.5 mg/d) and 5.7 mg/d (range: 2.7-14 mg/d). Compared to the provisional tolerable weekly intake (PTWI) of 25 micrograms/(kgbw x week) proposed by the WHO the dietary intake of lead was low. The median amounted to 8.5% and the maximum to 20% of the PTWI. The cadmium intake was comparatively high. The median amounted to 39% and the maximum to 63% of the PTWI [7 micrograms/(kgbw x week)]. The median intake of copper was in the range of the values recommended by the German Society of Nutrition (0.7-1.0 mg/d and 1.0-1.5 mg/d for children at the age of 1-< 4 years and 4-< 7 years). Twenty-three percent of the calculated intakes were below these values. The median intake of zinc however did not reach the recommended dietary intake of 7 and 10 mg/d for children at the age of 1-< 4 years and 4-< 7 years.

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.

Psychosocial factors in the occurrence of environmental intolerances.

The phenomenon referred to as environmental illness, especially multiple chemical sensitivity, is an extremely controversial and puzzling issue. Despite the seeming gestalt of the disease there is no objective measure for diagnosis and pathophysiology. Psychological and psychosocial factors have a significant role in the presentation and prospects of the disease. Medical neglect of the suffering of the patients as well as iatrogenic attribution towards a chemical intoxication might both increase the risk of chronification and social isolation of patients up to a point of no return. Several observations and results from studies with environmental patients and in related fields are presented and discussed with the aim to encourage continuous research and a critical approach towards a phenomenon where the political necessity to decide is more advanced than the ability to understand.

Behavioral effects following single and combined maternal exposure to PCB 77 (3,4,3',4'-tetrachlorobiphenyl) and PCB 47 (2,4,2',4'-tetrachlorobiphenyl) in rats.

The present study has compared the neurobehavioral effects of two structurally different PCB congeners or their combination in rats. Time-mated Long-Evans rats received daily injections of the coplanar PCB 77 (3,4 3',4'-TCB: 0.5 or 1.5 mg/kg), the di-ortho-chlorinated PCB 47 (2,4,2',4'-TCB: 1.5 mg/kg) or a congener mixture (0.5 mg/kg PCB 77 + 1.0 mg/kg PCB 47) from day 7 to 18 of gestation. The PCB exposure levels in brain and perirenal fat of dams and offspring were determined by GC/ECD on gestational day 19 (GD 19), postnatal day 21 (PND 21), and PND 45. PCB 77 was accumulated to a smaller degree than PCB 47. On GD 19, PCB 77 was found to a greater extent in the brains of the offspring than in the brains of the dams, whereas the level of PCB 47 was almost the same in dams and offspring. The testing of open-field behavior in male rats on PND 18 and PND 70 revealed an altered distribution of activity with enhanced activity in the inner zone in PCB 77-treated rats compared to all other groups, while the overall activity was not changed. Distance traveled and rearing behavior on PND 340 were elevated relative to controls in all PCB-treated groups, indicating age-related effects of maternal exposure. A step-down passive avoidance task revealed decreased latencies in the PCB 77 and combined exposure groups on PND 80. Only PCB 77-treated animals showed increased latencies on PND 100 on the haloperidol-induced catalepsy test. These results indicate long-term effects of maternal exposure to PCB 77 on emotional and motor functions. At the dose levels used in the present experiments, the two congeners given in combination did not cause additive or synergistic effects. Instead, concurrent exposure to PCB 47 seemed to counteract PCB 77-induced changes in the pattern of activity.

Organochlorine pesticides and polychlorinated biphenyls in human milk of mothers living in northern Germany: current extent of contamination, time trend from 1986 to 1997 and factors that influence the levels of contamination.

This study reports the concentration levels of PCB, DDT, HCB and beta-HCH in the human milk of women living in northern Germany over a period of 12 years and determines factors that may influence these levels. From 1986 to 1997 more than 3500 milk samples were analyzed for organochlorine compounds. A questionnaire was used to obtain information regarding personal characteristics, life style factors and eating habits. Descriptive statistics of concentration levels were computed to characterize the current extent of contamination. To follow time trends across the years homogeneous subgroups were compared and multiple regression analyses were used to investigate associations between determining factors and specific contaminants. Between summer 1995 and summer 1997 the median PCB concentration level was 0.502 mg/kg, the median DDT level 0.202 mg/kg, the median HCB level 0.065 mg/kg and the median beta-HCH level 0.036 mg/kg, all values expressed on a fat basis. The median concentration levels decreased by 80-90% during the past 12 years and the median PCB levels by 60%. The concentration levels of all substances were positively correlated with maternal age and negatively associated to parity, to the total period of breast-feeding and to a weight increase of mothers before and after delivery. Post-pregnancy BMI was a significant predictor of the likelihood of having higher concentrations for DDT, HCB and beta-HCH and of having lower concentrations for PCB levels. A balanced diet for at least 3 years was related to lower HCB and beta-HCH levels. Women who ate more than 100 g of fish or more than 700 g of meat per week were more likely to have higher PCB and beta-HCH levels or higher HCB levels, respectively. Higher HCB and beta-HCH concentration levels were associated with lower birth weights of female infants.

Developmental neurotoxicity of polychlorinated biphenyls (PCBS): cognitive and psychomotor functions in 7-month old children.

Neurobehavioral effects of polychlorinated biphenyls (PCBs) at environmental levels of exposure have been reported in cross-sectional and prospective studies in infants and children. However, observations differ for effect spectrum, persistence and effective matrix (cord plasma, maternal plasma or milk). In order to improve risk assessment by clarifying some of these uncertainties, a European multicentric study was set up. Results from the German (Düsseldorf) cohort covering 171 healthy mother-infant pairs are given. The sum of PCB congeners 138, 153 and 180 (sigma PCB) in cord plasma and maternal milk was used to describe neonatal PCB exposure. Mean sigma PCB-concentrations were 0.55 ng/ml in cord plasma and 427 ng/g fat in breastmilk. This report covers the Bayley II mental (MDI) and psychomotor development index (PDI) as well as the Fagan Test of Infant Intelligence (Visual Recognition Memory) taken at 7 months of age in relation to neonatal sigma PCB. After confounder-adjustment significant negative associations were found between sigma PCB in milk and MDI (P < 0.05), whereas the other associations proved insignificant.

Sample collection guidelines for trace elements in blood and urine. IUPAC Commission of Toxicology.

This paper presents an organized system for element-specific sample collection and handling of human blood (whole blood, serum or plasma, packed cells or erythrocytes) and urine also indicating a proper definition of the subject and sample. Harmonized procedures for collection, preparation, analysis and quality control are suggested. The aim is to assist scientists worldwide to produce comparable data which will be useful on a regional, national and international scale. The guidelines are directed to the elements aluminium, arsenic, cadmium, chromium, cobalt, copper, lead, lithium, manganese, mercury, nickel, selenium and zinc. These include the most important elements measured for their occupational or clinical significance, and serve as examples of principles that will guide development of methods for other elements in the future.

Impairment of schedule-controlled behavior by pre- and postnatal exposure to hexachlorobenzene in rats.

Hexachlorobenzene (HCB) is still frequently found at elevated levels in human adipose tissue and breast milk. As intoxication with HCB causes neurological disturbance in human beings, the purpose of the present study was to examine neurobehavioral functions in rats after pre- and postnatal exposure. Female rats were fed diets with 0, 4, 8, or 16 mg HCB/kg diet. Exposure started 90 days prior to mating and was continued throughout mating, gestation, and lactation. Thereafter, the offspring were given the same diets as their respective mothers. HCB levels were determined in the brain, the liver, and in the adipose tissue from virgin rats, dams, and the offspring. Concentrations on a lipid basis were found to decline in the order adipose > liver > brain. The exposure levels chosen did not cause gross toxic effects in dams or offspring. There were dose-related increases in liver-to-body-weight ratios in exposed dams, but not in unmated females treated alike. Behavioral testing was conducted in the offspring. Examination of open-field activity on PND 21, and of active avoidance learning on PND 90 failed to reveal significant differences between groups. Training of operant behavior started at the age of 150 days in the offspring from the control, the 8-mg group, and the 16-mg group. Animals were trained on a fixed interval schedule of 1 min (FI-1). On this schedule, responses were reinforced by a food pellet every time 1 min had elapsed after the preceding reinforcement. There were dose-dependent reductions in the post-reinforcement pause, e.g. the time between each reinforcement and the first reaction emitted after it. In addition, the index of curvature, which describes the efficiency of performance on the FI-1 schedule, was decreased in a dose-dependent fashion.

Long term exposure to manganese in rural well water has no neurological effects.

BACKGROUND: There is debate on the neurological impact of chronic exposure to Manganese (MN). METHODS: MN burden from rural well water was studied cross-sectionally in two proband cohorts from rural dwellings located in northern Germany. Both cohorts had exposure times for up to 40 years and were separated on the basis of well water MN content. Group A (41 subjects; mean age 57.5 years) was exposed to MN water contents of at least 0.300 mg/l (range 0.300 to 2.160), while group B (74 subjects; mean age 56.9 years) was exposed to concentrations of less than 0.050 mg/l. Both proband groups were homogenous with regard to age, sex, nutritional habits, and drug intake. Neurological assessments by clinical investigators blinded for proband's exposure status was done using structured questionnaires, standardized neurological examination with assessment of possible Parkinsonian signs by the Columbia University Rating Scale, and instrumental tests of fine motor coordination. RESULTS: No significant difference in any neurological measure was found between groups. Results were not confounded by demographic and dietary features. CONCLUSION: Exposure to high body burden of MN does not result in detectable neurological impairment. Exposure to MN in drinking water does not seem to be a risk factor for idiopathic Parkinson's disease.

[Burden of DDT, HCH, HCB and PCB in human milk in the former German Democratic Republic. Research and toxicologic evaluation]. / Belastung der Humanmilch in der ehemaligen DDR mit DDT, HCH, HCB, PCB. Untersuchung und toxikologische Bewertung.

The decreasing tendency of the contamination of human milk with residues of organochlorine compounds (DDT, HCH, HCB, PCB) has been confirmed by our investigations also for the territory of the former GDR. Compared with the residue-situation existing in the FRG, the contamination of breast milk with DDT-metabolites 4,4'-DDE and 4,4'-DDT were elevated. A positive correlation was found between age and HCB-exposure, urban residency and 4,4'-DDE, beta-HCH and PCB, and smoking and beta-HCH-residues in human milk.

Critical evaluation of current concepts in exposure assessment.

The exploitation of natural resources and the improper use and disposal of thousands of chemicals have resulted in environmental pollution and a potential threat to human health on a global scale. Increasing public concern about environmental exposure to and consequent ill health from contaminants demands informed answers based on valid risk assessment. By assessing internal exposure to pollutants, human biomonitoring focuses on early markers of potential risks to prevent serious adverse effects. Exposure assessment may provide a rational basis for risk assessment, with knowledge of the adequacy of limit values; it may also uncover long-term changes in body burdens and thus help identify the sources and transfer pathways of environmental pollutants. The techniques of biological exposure assessment should be incorporated into epidemiological studies if suitable specimens are available, such as exhaled air, blood, urine, breast milk, or adipose or keratinous tissue. Special precautions must be taken in sampling, storage, and analysis if the findings are to be interpreted correctly and reliable conclusions drawn.

[Formic acid in urine--a significant parameter in environmental diagnosis?]. / Ameisensäure im Urin--ein sinnvoller Parameter der umweltmedizinischen Diagnostik?

Reference intervals of formic acid excretion in urine of healthy occupational unexposed adults were determined. Within the range of specific gravity between 1.016-1.032 g/cm3 normalization by creatinine or gravity is unnecessary. The mean formic acid concentration in urine of female and male adults aged 20-80 years was 21 mg/l +/- 30 mg/l (95. percentile 60 mg/l) with slightly higher values in elder persons. Smoking and dietary habits had no influence on formic acid excretion but age was positively correlated with increased concentrations. An oral methanol intake of 10 mg/kg body weight had no significant impact on urine excretion of formic acid. Excretion in the general population is determined by endogenous metabolism of amino acids, purine- and pyrimidine-bases rather than the uptake and metabolism of precursors like formaldehyde. Hence in contrast to recent recommendations in environmental medicine, formic acid in urine is not an appropriate parameter for biological-monitoring of low level exposure to formaldehyde.

Internal exposure to organic substances in a municipal waste incinerator.

Fifty-three persons occupied in a municipal waste incinerator were examined with respect to their internal exposure to organic substances which may be produced during pyrolysis of organic matter. For this purpose the levels of benzene in blood, polychlorinated biphenyls (PCBs) and hexachlorobenzene (HCB) in plasma, and mono- (MCPs), di- (DCPs), tri- (TCPs), tetra- (TCEPs) and pentachlorophenol (PCP) and hydroxypyrene in urine were determined. For control purposes, 431 men and women were examined. Significantly higher values for the workers were found for the excretion of hydroxypyrene [median (m): 0.24 vs 0.11 microgram/l; non-smokers], 2,4/2,5-DCP (m: 10.5 vs 3.9 micrograms/l) and 2,4,5-TCP (m: 1.2 vs 0.8 micrograms/l) and for the HCB level in plasma (m: 4.4 vs 2.8 micrograms/l). For the concentrations of 4-MCP and 2,3,4,6/2,3,5,6-TECP, the controls had significantly higher concentrations in urine than did the workers in the incineration plant (m: 4-MCP 1.7 vs 1.2; 2,3,4,6/2,3,5,6-TECP: 1.2 vs 0.3 micrograms/l). No significant differences between workers and controls were detected with respect to benzene in blood (m: 0.20 vs 0.28 microgram/l; non-smokers), 2,4,6-TCP and PCPs in urine (m: 0.85 vs 0.60 and 2.2 vs 2.2 micrograms/l) or the levels of PCB congeners in plasma (m: sigma 138, 153, 180: 5.6 vs 4.1 micrograms/l). The elevated levels of hydroxypyrene, 2,4/2,5-DCP, 2,4,5-TCP and HCB in biological material may be related to the incineration of the waste. These elevations, however, are very small and are of interest more from the environmental than from the occupational point of view.