G.W. ten Tusscher

Effects of Dioxins, PCBs, and PBDEs on Immunology and Hematology in Adolescents

Dioxins and PCBs are environmental pollutants, proven to be immunotoxic. In the period 1987-1991 a cohort of mother-baby pairs was initiated to detect abnormalities in relation to dioxin levels in the mothers milk. At birth and at follow-up at 8-12 years, immunological and hematological effects were seen, prompting us to perform a new follow-up during adolescence. In addition, we assessed the immunological and hematological parameters in relation to current levels of PBDEs and PCBs. In the Netherlands, the pre- and postnatal exposure to dioxins have been studied prospectively since 1987. Venapuncture was performed to assess hematological (Hemoglobin, thrombocytes, thrombopoietin) and immunological (leukocytes, leukocyte differentiation) parameters and the current serum levels of dioxin, dioxinlike (dl)-PCBs and PBDEs. A decrease in the number of polymorphic neutrophils was found in adolescents with higher dl-PCBs in their serum (p = 0.021). No relation with total leukocytes, thrombocytes, hemoglobin, or thrombopoietin levels was seen. Similarly, we found no relation between prenatal, nor current dioxin levels and the hematological and the immunological parameters determined. The SigmaPBDEs were negatively associated with the number of lymphocytes (p = 0.01) and positively associated with the hemoglobin concentration (p = 0.003). These effects on the innate immunity by current levels of dl-PCBs and on the adaptive immunity by PBDEs are disconcerting, especially as the dl-PCB (0.04-7.8 WHOTEQ pg/g lipid, mean: 2.2 WHOTEQ pg/g lipid) and SigmaPBDE levels (mean 14.0 ng/g lipid, including one outlier with a sum of 73.6 ng/g lipid) were not high.

Decreased lung function associated with perinatal exposure to Dutch background levels of dioxins

Perinatal exposure to Dutch background dioxin levels is rather high. Studies of calamities have shown that dioxins negatively influence the respiratory system. It was hypothesized that perinatal exposure to background dioxin levels leads to lung suboptimality, probably through developmental interference. This study aimed to assess lung function in relation to perinatal dioxin exposure. Spirometry was performed in 41 healthy children (aged 7‐12 y, mean 8.2 y) with known perinatal dioxin exposure. The ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC ratio) was determined. A complete medical history was taken. The prenatal exposure ranged from 8.74 to 88.8 (mean 34.6) ng TEQ dioxin kg fat−1, measured in breast milk. The postnatal exposure ranged from 4.34 to 384.51 (mean 75.4) ng TEQ dioxin. Twelve children had to be excluded. A significant decrease in lung function in relation to both prenatal (p= 0.045) and postnatal (p= 0.0002) dioxin exposure was seen in the 29 non‐excluded children. A clinical association between chest congestion and perinatal dioxin exposure was seen.

Assessment of current serum levels of PCDD/Fs, dl-PCBs and PBDEs in a Dutch cohort with known perinatal PCDD/F exposure

As part of a longitudinal cohort study, now in its second decade, we determined PCDDs/Fs dl-PCBs and PBDEs in serum of adolescents with known perinatal PCDD/F exposure. Of the original cohort, 33 adolescents aged 14-19 years, who had been studied previously during their neonatal (n=60), toddler and pre-pubertal period (n=41) agreed to participate in the current follow-up. PCDD/F-, dl-PCB- and PBDE congeners were measured using GC/MS. Current serum levels of PCDD/Fs determined in our cohort were relatively low (mean of 2.2 pg/g) compared to the perinatal exposure. No correlation between perinatal exposure and current serum PCDD/F was found. Planar PCB TEQ levels were 2.2 pg/g. Current summation operatorPBDE levels were 8.7 ng/g lipid. There was one outlier with a summation operatorPBDE of 74 ng/g lipid. The presence of this high value indicates that the exposure pathway is different from PCDD/F and PCB, most likely by dust and food contaminated with dust. Concluding we can say that current PCDD/F levels are quite low compared to the perinatal PCDD/F exposure of the cohort. PBDE levels however are relatively high compared to other European countries, more research on possible health effects of these levels, especially for subjects with outlier concentrations, should be performed.

Validation of a high-performance liquid chromatography assay for quantification of caffeine and paraxanthine in human serum in the context of CYP1A2 phenotyping

In this study the validation of a reversed-phase high-performance liquid chromatography (HPLC) method, with UV-detection, for both caffeine and paraxanthine in human serum is described. This method is feasible for cytochrome P450 1A2 (CYP1A2) phenotyping, according to the results of a pilot study. With this HPLC method caffeine and paraxanthine can be determined selectively and specifically. In the expected concentration range, caffeine recoveries were 98-108% (within-run variation 4.0-6.4%, between-run variation 6.4-8.8%), paraxanthine recoveries were 96.6-97.5% (within-run variation 5.0-7.2%, between-run variation 7.2-10.8%). The limits of detection for caffeine and paraxanthine using this HPLC system were 0.3 and 0.1 mg/L, respectively. Linear calibration curves for both caffeine and paraxanthine were obtained in the concentration range 0.5-30 mg/L (r > 0.9999. Serum samples were stable for a week, when stored at -20 and +4 degrees C.

The influence of perinatal and current dioxin and PCB exposure on reproductive parameters (sex-ratio, menstrual cycle characteristics, endometriosis, semen quality, and prematurity): a review

Abstract Polychlorinated biphenyls (PCBs) and dioxins (PCDDs/Fs) are well-known endocrine disrupters. This paper strives to elucidate the data on reproductive consequences of perinatal dioxin and PCB exposure in men and women. We focused on the following end-points: sex-ratio, endometriosis, menstrual cycle characteristics, sperm quality, and prematurity. We summarize 46 papers and compare their results including effects seen after exposure to background concentrations. Seven of twelve studies showed a decrease in sex-ratio after parental dioxin or PCB exposure. In three of the seven studies, effects were seen after paternal exposure and in three after maternal exposure. In eight of the nine studies on menstrual cycle characteristics, abnormalities were associated with PCB or dioxin exposure, however the results differed. In three studies PCB and TCDD were associated with longer menstrual cycles, while three studies indicated that an increase in PCB/PCDF exposure was associated with shorter cycles. Five studies showed effects on menstrual bleeding with higher PCB or dioxin exposure. A higher rate of irregular menstrual cycles in exposed women was seen in four studies. The conflicting outcomes probably result from variability in study design, timing of exposure and endocrine disrupting properties of the measured congeners. Nine of sixteen studies detected higher PCB or dioxin exposure in women with endometriosis. However, the manner of diagnosing endometriosis and the character of the studies varied from prospective to retrospective. Five of eight studies focusing on sperm quality showed that men, with higher serum concentrations of PCBs and/or PCB congeners and/or PCDFs, had reduced sperm quality, including increased abnormal morphology and reduced motility. The exposure timeframe seemed important here. There are two studies addressing preterm birth in relation to PCBs, one mentioned a shortening of three days of gestational age, two other studies did not find a relation. Recently one study related a shorter gestational age of half a week with overall dioxin activity measured with the CALUX method in cord blood, particularly in boys. In conclusion, exposure to PCBs and dioxins has a negative effect on the reproductive systems of human populations. Although some speculations have been made, the exact mechanism of these effects and the interactions of these compounds with other endocrine disruptors are not yet known. Age at exposure and congener specific properties are probably crucial in interpreting the observed results.

The influence of perinatal and current dioxin and PCB exposure on puberty: a review

Abstract Over the last two decades much has been written about the consequences of perinatal dioxin and PCB exposure in humans. In this paper we strive to elucidate the data on puberty in relation to these endocrine disruptive compounds in human populations. Effects in PCB/dioxin-exposed human populations on puberty are seen, not only in highly exposed cohorts, but also in average populations with background exposures. Study showed effects like increased weight, a delay in pubic hair growth and male genital development in boys, sex-hormone homeostasis, reduced penile length, and delayed age at first ejaculation after PCB exposure. Effects seen after dioxin exposure include retarded initiation and stage of breast development in girls, earlier menarche, disruption of sex hormone homeostasis, reduced testicular volume and reduced penile length in boys. The data published by different studies were inconclusive as a result of different methodological setup as well as because of multiple exposure settings. Populations were exposed to different mixtures of dioxin/PCB congeners or mixtures with other endocrine disrupters, and therefore synergistic and antagonistic effects with PCBs and dioxins are possible. Dioxinlike compounds disturb the hormonal balance mainly through interaction with the Ah receptor, which may influence the synthesis of hormones or their transport proteins. However, we have to keep in mind that hormonal balance during puberty could also be altered by disruption of the thyroid homeostasis. Another important possible mechanism is the induction of epigenetic changes or effects on genetic polymorphism. The fact that exposure to background concentrations of dioxin-like compounds and PCBs also has effects on the reproductive development is disconcerting and warrants further research and long term follow-up studies.

A Local Increased Incidence of Orofacial Clefts in Amsterdam: The Result of Open Combustion of Chemicals?

The open chemical combustions in Zeeburg, Amsterdam, the Netherlands, from the year 1961 up to and including 1969 resulted in a local increased incidence of orofacial clefts during this period.

Background Exposure to Dioxins and PCB’s in Europe and the Resulting Health Effects

The effect of exposure to background levels of dioxins and PCB s transplacentally and through breast-feeding on healthy new-born babies after an optimal pregnancy were studied in the Netherlands.

Comment on: Prenatal exposure to acid‐suppressive drugs and the risk of allergic disease in the offspring: a cohort study

Comment on: Prenatal exposure to acid-suppressive drugs and the risk of allergic disease in the offspring: a cohort study N. C. M. Petrus, Y. E. M. Thomasse, A. B. Sprikkelman, W. M. C. van Aalderen and G. W. ten Tusscher Department of Paediatrics and Neonatology, Westfriesgasthuis, Hoorn, the Netherlands and Department of Paediatric Respiratory Medicine and Allergy, Emma Children’s Hospital AMC, Amsterdam, the Netherlands