Per Ola Darnerud

Toxic effects of brominated flame retardants in man and in wildlife

Brominated flame retardants (BFRs) are ubiquitous industrial chemicals, and many of them are produced in large volumes. Due to this fact, several BFRs are found in quantifiable levels in wildlife, as well as in humans. However, we are still lacking information on the effects of BFR in wildlife and, especially, in man. This review summarises the biological effects of polybrominated diphenyl ethers (PBDEs), tetrabromobisphenol A (TBBPA) and derivates, hexabromocyclododecane (HBCD) and polybrominated biphenyls (PBBs), however excluding other aspects such as environmental levels. These BFR groups were selected because of a large volume production (PBDEs, TBBPA and derivates), and availability of some toxicity data in spite of much lower production volumes (HBCD and PBBs). In addition, the increase in levels of PBDEs in human (breast milk) and wildlife samples during later time made it especially interesting to include this BFR group. PBDES: The commercial PBDE products predominantly consist of so-called penta-, octa- and decabromodiphenyl ether products. Each product consists of a rather narrow range of congeners and is named after the dominating congener as regards the bromination pattern. Generally, the PentaBDEs seem to cause adverse effects at the comparably lowest dose, whereas much higher doses were needed for effects of the DecaBDEs. The critical effects of PentaBDEs are those on neurobehavioural development (from 0.6 mg/kg body weight) and, at somewhat higher dose, thyroid hormone levels in rats and mice, of OctaBDEs on fetal toxicity/teratogenicity in rats and rabbits (from 2 mg/kg body weight), and of DecaBDEs on thyroid, liver and kidney morphology in adult animals (from 80 mg/kg body weight). Carcinogenicity studies, only performed for DecaBDEs, show some effects at very high levels, and IARC (1990) evaluates DecaBDEs not classifiable as to its carcinogenicity to humans. TBBPA: The toxicity of TBBPA in the experimental in vivo studies is suggested to be low. In most reported studies, only doses in g/kg body weight were effective, but at least one study suggested renal effects at around 250 mg/kg body weight. Although difficult to include and interpret in a quantitative risk assessment, the in vitro effects on immunological and thyroid hormones, as well as binding to erythrocytes should be noted. Before a solid standpoint could be reached on TBBPA toxicity additional studies must be performed. This statement is even more valid regarding the TBBPA derivates, where there is an almost complete lack of toxicity data. HBCD: Also in the case of HBCD, relevant toxicity studies are lacking. Based on the present animal studies, a critical effect is seen in the liver and on thyroid hormones (LOAEL 100 mg/kg body weight/day). However, in a recent short paper behavioural effects in mice pups were observed already at 0.9 mg/kg body weight, and behavioural effects may be a sensitive endpoint for HBCD, as well as for other BFRs. PBBS: Due to the Michigan accident in 1973-1974, many toxicity studies on PBBs are available. The critical experimental effects are those on reproduction and carcinogenicity, and a NOAEL of 0.15 mg/kg body weight/day could be suggested based on the cancer effects. In man no unequivocal effects have been observed, although in some studies neurological and musculoskeletal symptoms were suggested. Based on the carcinogenic effects in animals, a human TDI of 0.15 microg/kg body weight has been presented. To conclude, the toxicity data are almost entirely based on experimental models. There are differences among the BFR groups, as well as within these groups, both regarding type of toxic effect and at what dose it appears. As BFRs will continue to appear both in industrial applications and, even if the production has ceased, in our environment, there is a continued need for effects studies on BFRs.

Exposure of Perfluorinated Chemicals through Lactation: Levels of Matched Human Milk and Serum and a Temporal Trend, 1996–2004, in Sweden

Background Only limited data exist on lactation as an exposure source of persistent perfluorinated chemicals (PFCs) for children. Objectives We studied occurrence and levels of PFCs in human milk in relation to maternal serum together with the temporal trend in milk levels between 1996 and 2004 in Sweden. Matched, individual human milk and serum samples from 12 primiparous women in Sweden were analyzed together with composite milk samples (25–90 women/year) from 1996 to 2004. Results Eight PFCs were detected in the serum samples, and five of them were also above the detection limits in the milk samples. Perfluorooctanesulfonate (PFOS) and perfluorohexanesulfonate (PFHxS) were detected in all milk samples at mean concentrations of 0.201 ng/mL and 0.085 ng/mL, respectively. Perfluorooctanesulfonamide (PFOSA), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) were detected less frequently. Discussion The total PFC concentration in maternal serum was 32 ng/mL, and the corresponding milk concentration was 0.34 ng/mL. The PFOS milk level was on average 1% of the corresponding serum level. There was a strong association between increasing serum concentration and increasing milk concentration for PFOS (r2 = 0.7) and PFHxS (r2 = 0.8). PFOS and PFHxS levels in composite milk samples were relatively unchanged between 1996 and 2004, with a total variation of 20 and 32% coefficient of variation, respectively. Conclusion The calculated total amount of PFCs transferred by lactation to a breast-fed infant in this study was approximately 200 ng/day. Lactation is a considerable source of exposure for infants, and reference concentrations for hazard assessments are needed.

Perfluorinated Alkyl Acids in Blood Serum from Primiparous Women in Sweden: Serial Sampling during Pregnancy and Nursing, And Temporal Trends 1996–2010

We investigated temporal trends of blood serum levels of 13 perfluorinated alkyl acids (PFAAs) and perfluorooctane sulfonamide (FOSA) in primiparous women (N = 413) from Uppsala County, Sweden, sampled 3 weeks after delivery 1996-2010. Levels of the short-chain perfluorobutane sulfonate (PFBS) and perfluorohexane sulfonate (PFHxS) increased 11%/y and 8.3%/y, respectively, and levels of the long-chain perfluorononanoate (PFNA) and perfluorodecanoate (PFDA) increased 4.3%/y and 3.8%/y, respectively. Concomitantly, levels of FOSA (22%/y), perfluorooctane sulfonate (PFOS, 8.4%/y), perfluorodecane sulfonate (PFDS, 10%/y), and perfluorooctanoate (PFOA, 3.1%/y) decreased. Thus, one or several sources of exposure to the latter compounds have been reduced or eliminated, whereas exposure to the former compounds has recently increased. We explored if maternal levels of PFOS, PFOA, and PFNA during the early nursing period are representative for the fetal development period, using serial maternal serum samples, including cord blood (N = 19). PFAA levels in maternal serum sampled during pregnancy and the nursing period as well as in cord blood were strongly correlated. Strongest correlations between cord blood levels and maternal levels were observed for maternal serum sampled shortly before or after the delivery (r = 0.70-0.89 for PFOS and PFOA). A similar pattern was observed for PFNA, although the correlations were less strong due to levels close to the method detection limit in cord blood.

Polybrominated diphenyl ethers in breast milk from Uppsala County, Sweden☆

The breast milk concentrations of polybrominated diphenyl ethers (PBDEs; sum of five congeners: BDE-47, -99, -100, -153, and -154) were determined (by GC-ECD) in samples from 93 primiparous women collected from 1996 to 1999 in Uppsala County, Sweden. Dietary and lifestyle factors were also recorded. The mean PBDE concentration was 4.0 ng/g fat and the distribution of samples was skewed with few high values (maximum 28.2 ng/g fat). BDE-47 was the major congener and constituted 59% of the mean concentration of PBDEs. No significant relationship was found between breast milk concentrations of PBDEs and dietary intake of PBDE, age, body mass index, alcohol consumption, or computer usage. After adjustments for these factors, a weak but significant association between PBDE concentrations and smoking was observed. The dietary intake of PBDE for these women was estimated at 27 ng/day, of which fish contributed almost half. After inclusion of 31 additional samples, collected from 2000 to 2001, time trends were studied. The changes in breast milk PBDE levels between 1996 and 2001, similar to the results from another Swedish study on milk from Stockholm mothers, suggest a peak in PBDE concentrations around 1998 and thereafter decreasing levels. However, far-reaching conclusions about PBDE time trends in milk cannot be drawn from this short study.

Persistent organochlorine and organobromine compounds in mother's milk from Sweden 1996-2006: compound-specific temporal trends.

High body burdens of persistent halogenated organic pollutants (POPs) among pregnant and nursing women are of concern because of exposure of the growing foetus and breast-feeding infant. We examined the temporal trends of polychlorinated biphenyls (PCBs), dibenzo-p-dioxin (PCDDs) and dibenzofurans (PCDFs), polybrominated diphenyl ethers (PBDEs) and hexabromocyclododecane (HBCD) in milk samples from Swedish women. POPs were analysed in individual mothers milk samples from randomly recruited primiparas (N=335) who lived in Uppsala County and delivered between 1996 and 2006. Results were adjusted for life-style factors that are associated with POP body burdens. PCB levels declined 3.9-8.6% per year. The levels of PCDDs decreased faster (6-9% per year) than the levels of PCDFs (3-6% per year). Temporal trends of PBDEs did not follow any consistent pattern. Concentrations of BDE-47 and BDE-99 decreased, while the concentrations of BDE-153 increased. No change in BDE-100 concentrations was observed. In most samples, concentrations of HBCD were below the quantification limit (<0.20 ng/g lipid). Generally, adjustment of the temporal trends of PCBs and PCDD/Fs for personal characteristics of the mothers (age, body mass index (BMI), weight changes during and after pregnancy) resulted in faster declining rates, with age having the greatest influence. The age of the participating mothers increased during the study period, and since the POP levels increased with increasing age, this counteracted the decreasing temporal trends in the unadjusted model. It is consequently important to include personal characteristics in the analysis of temporal trends of POPs. Compound-specific temporal trends are probably caused by differences in sources of exposure, as well as by differences in persistence between compounds.

PCDD/F, PCB, PBDE, HBCD and chlorinated pesticides in a Swedish market basket from 2005--levels and dietary intake estimations.

Based on consumption data statistics, food items from four regions in Sweden were sampled in a so-called market basket study. Food items from five food groups, i.e. fish, meat, dairy products, eggs and fat/oils, were analyzed for persistent organic pollutants (POPs) followed by per capita intake calculations. The highest levels of PCDD/F, PCB, PBDE, HBCD and chlorinated pesticides were found in the fish/fish products. The estimated market basket per capita intake of PCDD/F and dl-PCB was 0.7pg WHO-TEQ kg bw(-1) d(-1) (TEFs from 1998). The intake of ∑PCB was estimated to 4.9 ng kg bw(-1) d(-1) and fish was found to be the major contributor with 64%. The intake of ∑PBDE was found to be 0.7 ng kg bw(-1) d(-1). Fish (38%) and dairy products (31%) were the largest contributors to the total PBDE intake. The intake of HBCD was estimated to 0.14 ng kg bw(-1) d(-1). HBCD mainly came from fish (65%), but also dairy products (24%) and meat (10%) contributed. Also regarding the chlorinated pesticides, fish was found to be the major contributor, with 51% of the ∑DDT coming from fish. The intake of ∑DDT, ∑HCH and HCB was 4.0, 1.0 and 1.1 ng kg bw(-1) d(-1), respectively. Most of the ∑HCH and HCB originate from dairy products (43% and 55%, respectively). This study shows that the levels, and intake, of different POPs from food of animal origin in the market basket of 2005 seem to have decreased since the market basket study in 1999.

Lead, mercury, and cadmium in blood and their relation to diet among Swedish adults

The aim of the present study was to examine the body burden of lead (Pb), mercury (Hg), and cadmium (Cd) in blood among Swedish adults and the association between blood levels, diet and other lifestyle factors. The study was based on a subgroup (n=273) of the national survey Riksmaten 2010-2011 (4-day food records and questionnaire). Lead, Hg, and Cd were measured in whole blood, and Cd additionally in urine, by mass or fluorescence spectrometry methods. The median values (5-95th percentiles) of the metals in blood were as follows; Pb: 13.4 (5.8-28.6) μg/L, Hg: 1.13 (0.31-3.45) μg/L, and Cd: 0.19 (0.09-1.08) μg/L. All three metals increased with increasing age. Lead levels in blood were positively associated with intakes of game and alcohol, Hg was related to fish intake, and blood Cd related to smoking and low iron stores and to a low meat intake. Body burdens of the studied metals were generally below health based reference values, but several individuals had blood Pb levels above the reference point for possible nephrotoxic and developmental neurotoxic effects. As health effects cannot be excluded, individuals with high Pb exposure should aim at decreasing their body burden, both from food and from other exposure routes.

4-Nonylphenol and bisphenol A in Swedish food and exposure in Swedish nursing women

4-Nonylphenol (NP) and bisphenol A (BPA) are phenolic substances used in high volumes by the industry. Studies on cells and in experimental animals have shown that both these compounds can be classified as estrogenic hormone disrupters. Information about the exposure of humans to NP and BPA is still scarce, especially regarding levels in human blood. The first aim of this study was to investigate possible sources of NP and BPA exposure from food, by analyzing the levels of NP and BPA from a Swedish food market basket, based on the Swedish per capita food consumption. A second aim was to investigate blood serum levels of NP and BPA, as well as NP-ethoxylates, among young women in Sweden (n=100). Moreover, associations between food consumption and blood NP and BPA levels were studied. In food, NP was to some extent found at levels above limit of quantification (LOQ 20 ng/g fresh weight) in fruits, cereal products, vegetables, and potatoes. BPA levels above LOQ (2 ng/g fresh weight) were found in fish, meats, potatoes, and dairy products. The estimated mean intakes per capita were (medium bound) 27 μg NP/day and 3.9 μg BPA/day, showing that food is a source of BPA and NP in the general Swedish population. In blood serum, free NP above limit of detection (LOD 0.5 ng/g) was detected in 46% of the study participants while detectable levels of total NP (LOD 0.8 ng/g) were observed in 43%. The corresponding percentages for BPA were 25% and 22%, respectively. The results indicate that there is a continuous source of exposure to NP and BPA that is high enough for free NP and BPA to be detected in some consumers. Among the participants with quantifiable levels of free and total NP (n=38), 85% (median, range: 38-112%) of the NP was present as free NP. For BPA 76% (49-109%) was detected as free BPA (n=15). All women had levels of ethoxylates of NP below LOD (0.1-0.7 ng/g). A significantly higher total consumption of fruits and vegetables was reported in questionnaires by participants with NP levels at or above LOD than among women with levels below LOD. This result is supporting the market basket results of relatively high NP levels in these types of food.

Levels of brominated flame retardants and other pesistent organic pollutants in breast milk samples from Limpopo Province, South Africa.

The non-occupational exposure to brominated flame retardants, and other persistent organic pollutants (POPs) was studied by collecting human breast milk samples from mothers residing in Thohoyandou area, a rural district in the Limpopo Province, northern part of South Africa (SA). Of all collected samples to be analysed (n=28), those with large enough milk volumes, (n=14) were quantified for polybrominated diphenyl ethers (PBDEs) (9 congeners: BDE-28, 47, 66, 99, 100, 138, 153, 154, and 183) and hexabromocyclododecane (HBCD) on a GC equipped with dual capillary columns and dual electron-capture detectors (ECD). The levels of PBDE congeners (median sumBDE 1.3 ng/g of lipids) and of HBCD were not far from levels generally found in European studies, and this study may be the first report on the presence of PBDEs and HBCD in SA breast milk. On a congener basis, the finding of comparably high BDE-183 levels suggests a specific PBDE usage, or contamination situation in SA. Apart from BFRs, the high DDT levels found in the breast milk from this area (median and maximum sumDDT levels of about 4600 and over 20,000 ng/g of lipids, respectively; n=28) have earlier been reported. In addition, other POPs (PCBs, HCB and HCHs) were found in SA breast milk, at relatively low levels. To conclude, measurable levels of PBDEs and HBCD, and a specific BDE congener pattern, were found in breast milk from the Limpopo province, SA. A number of other POPs, including DDTs in high levels, were also present.

Prenatal exposure to polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) may influence birth weight among infants in a Swedish cohort with background exposure: a cross-sectional study

BackgroundPrenatal exposure to persistent organic pollutants, e.g. polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) has been suggested to negatively affect birth weight although epidemiological evidence is still inconclusive. We investigated if prenatal exposure to PCBs and PBDEs is related to birth weight in a Swedish population with background exposure.MethodsBreast milk was sampled during the third week after delivery from first-time mothers in Uppsala county, Sweden 1996–2010 (POPUP cohort) (N = 413). Samples were analysed for di-ortho PCBs (CB-138, 153, 180) and tetra- to hexa- brominated PBDEs (BDE-47, 99, 100, 153). Simple and multiple linear regression models were used to investigate associations between lipid-adjusted, ln-transformed PCB and PBDE concentrations, and birth weight. Covariates included in the multivariate regression model were PCB and PBDE exposure, maternal age, pre-pregnancy BMI, weight gain during pregnancy, education, smoking, gender of the infant and gestational length. The effect of including fish consumption was also investigated.ResultsIn the multivariate model, prenatal exposure to di-ortho PCBs was significantly associated with increased birth weight (β = 137; p = 0.02). The result did not change when gestational length was added to the model. An inverse association between PBDE(4) (sum of BDE-47, -99, -100 and −153) and birth weight was observed in the multivariate model including gestational length (β = −106; p = 0.04). Maternal pre-pregnancy BMI and weight gain during pregnancy were important confounders of the association between di-ortho PCBs and birth weight. The associations were not alleviated after adjustment for fish consumption, a major source of PCB and PBDE exposure. The observed associations were stronger for boys than for girls.ConclusionsOur results indicate that prenatal exposure to di-ortho PCBs and PBDE(4) may influence birth weight in different directions, i.e. PCB exposure was associated with higher birth weight and PBDE exposure with lower birth weight. Maternal pre-pregnancy BMI and weight gain during pregnancy were important confounders that may hide positive association between di-ortho PCB exposure and birth weight if they are not included in the statistical model. We speculate that even small PCB- and PBDE-induced shifts in the distribution of birth weight may influence future public health in populations with background exposure.