For evaluation of internal exposure to harmful substances, the Human Biomonitoring Commission of the German Environment Agency (HBM Commission) develops toxicologically justified assessment values (HBM-I and HBMII). The HBM-I value corresponds to the concentration of a compound in human biological material below which no adverse health effects are expected to occur. Consequently, no action is required when the HBM-I value is not exceeded (HBM-Commission, 1996). In 2016, the HBM Commission developed HBM-I values of 2 ng PFOA/mL and 5 ng PFOS/mL in blood serum or plasma, respectively. A detailed delineation of supporting arguments was published in April 2018 (HBM-Commission, 2018). In contrast to the HBM-I, the HBM-II value corresponds to the concentration in human biological material which, when exceeded, may lead to health impairment which is considered as relevant to exposed individuals (HBM-Commission, 1996, HBM-Commission, 2014). HBM-II values for PFOA and PFOS: On September 17, 2019, the HBM Commission of the German Environment Agency established the following HBM-II values: Women at child-bearing age: 5 ng PFOA/mL blood plasma; 10 ng PFOS/mL blood plasma; All other population groups: 10 ng PFOA/mL blood plasma; 20 ng PFOS/mL blood plasma.

The detection of perfluoroalkyl substances (PFAS) in surface and drinking water from various countries raised the attention to the presence of these chemicals in environmental probes and led to several regulatory actions to limit exposure in human beings. There was particular concern about perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), due to their former wide-spread use. Recently, several institutions published revisions of former regulatory or recommended maximum concentrations in drinking water and food, which are markedly lower than the former values. The present short overview describes the current regulations for PFAS and compares them with the outcome of several experimental studies in laboratory animals at low-level exposure to PFOA and PFOS. In addition, regulations for short-chain PFAS are presented which, due to lack of toxicological information, are evaluated according to the concepts of Threshold of Toxicological Concern (TTC) or the Health-related Indication Values (HRIV).

PCB 180 is a persistent non-dioxin-like polychlorinated biphenyl (NDL-PCB) abundantly present in food and the environment. Risk characterization of NDL-PCBs is confounded by the presence of highly potent dioxin-like impurities. We used ultrapure PCB 180 to characterize its toxicity profile in a 28-day repeat dose toxicity study in young adult rats extended to cover endocrine and behavioral effects. Using a loading dose/maintenance dose regimen, groups of 5 males and 5 females were given total doses of 0, 3, 10, 30, 100, 300, 1000 or 1700 mg PCB 180/kg body weight by gavage. Doseresponses were analyzed using benchmark dose modeling based on dose and adipose tissue PCB concentrations. Body weight gain was retarded at 1700 mg/kg during loading dosing, but recovered thereafter. The most sensitive endpoint of toxicity that was used for risk characterization was altered open field behavior in females; i.e. increased activity and distance moved in the inner zone of an open field suggesting altered emotional responses to unfamiliar environment and impaired behavioral inhibition. Other dose-dependent changes included decreased serum thyroid hormones with associated histopathological changes, altered tissue retinoid levels, decreased hematocrit and hemoglobin, decreased follicle stimulating hormone and luteinizing hormone levels in males and increased expression of DNA damage markers in liver of females. Dose-dependent hypertrophy of zona fasciculata cells was observed in adrenals suggesting activation of cortex. There were gender differences in sensitivity and toxicity profiles were partly different in males and females. PCB 180 adipose tissue concentrations were clearly above the general human population levels, but close to the levels in highly exposed populations. The results demonstrate a distinct toxicological profile of PCB 180 with lack of dioxin-like properties required for assignment of WHO toxic equivalency factor. However, PCB 180 shares several toxicological targets with dioxin-like compounds emphasizing the potential for interactions. Citation: Viluksela M, Heikkinen P, van der Ven LTM, Rendel F, Roos R, et al. (2014) Toxicological Profile of Ultrapure 2,29,3,4,49,5,59-Heptachlorbiphenyl (PCB 180) in Adult Rats. PLoS ONE 9(8): e104639. doi:10.1371/journal.pone.0104639 Editor: Alok Deoraj, Florida International University, United States of America Received March 6, 2014; Accepted July 10, 2014; Published August 19, 2014 Copyright: 2014 Viluksela et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study was funded by the European Commission (ATHON (Assessing the toxicity and hazards of NDL-PCBs present in food), FOOD-CT-2005022923). The authors are solely responsible for the contents of this paper, which does not necessarily represent the opinion of the European Community. RR was also supported by the National Fund Research, Luxembourg (FNR) and co-funded under the Marie Curie Actions of the European Commission (FP7-COFUND), J. Toppari by the Academy of Finland and the Sigrid Jusélius Foundation and KH by Formas (2007-1524). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * Email: matti.viluksela@thl.fi

PCB 180 is a persistent non-dioxin-like polychlorinated biphenyl (NDL-PCB) abundantly present in food and the environment. Risk characterization of NDL-PCBs is confounded by the presence of highly potent dioxin-like impurities. We used ultrapure PCB 180 to characterize its toxicity profile in a 28-day repeat dose toxicity study in young adult rats extended to cover endocrine and behavioral effects. Using a loading dose/maintenance dose regimen, groups of 5 males and 5 females were given total doses of 0, 3, 10, 30, 100, 300, 1000 or 1700 mg PCB 180/kg body weight by gavage. Dose-responses were analyzed using benchmark dose modeling based on dose and adipose tissue PCB concentrations. Body weight gain was retarded at 1700 mg/kg during loading dosing, but recovered thereafter. The most sensitive endpoint of toxicity that was used for risk characterization was altered open field behavior in females; i.e. increased activity and distance moved in the inner zone of an open field suggesting altered emotional responses to unfamiliar environment and impaired behavioral inhibition. Other dose-dependent changes included decreased serum thyroid hormones with associated histopathological changes, altered tissue retinoid levels, decreased hematocrit and hemoglobin, decreased follicle stimulating hormone and luteinizing hormone levels in males and increased expression of DNA damage markers in liver of females. Dose-dependent hypertrophy of zona fasciculata cells was observed in adrenals suggesting activation of cortex. There were gender differences in sensitivity and toxicity profiles were partly different in males and females. PCB 180 adipose tissue concentrations were clearly above the general human population levels, but close to the levels in highly exposed populations. The results demonstrate a distinct toxicological profile of PCB 180 with lack of dioxin-like properties required for assignment of WHO toxic equivalency factor. However, PCB 180 shares several toxicological targets with dioxin-like compounds emphasizing the potential for interactions.

Whereas the effects of dioxin-like polychlorinated biphenyls (DL-PCBs) are well described, less is known about non-dioxin-like PCBs (NDL-PCBs), including influences on the nervous system and related behavioral effects after developmental exposure. Following the examination of the highly purified NDL congeners PCB52 and PCB180, we report here the results of experiments with PCB74 and PCB95. Rat dams were orally exposed to equimolar doses of either congener (40 μmol/kg bw – 11.68 mg PCB74/kg bw or 13.06 mg PCB95/kg bw) from gestational day (GD) 10 to postnatal day (PND) 7. Control dams were given the vehicle. Adult offspring were tested for cataleptic behavior after induction with haloperidol, a classical neuroleptic drug, and brainstem auditory evoked potentials (BAEPs), using clicks and tone pips of different frequencies for stimulation. Results revealed slight effects on latencies to movement onset in female offspring exposed to PCB74, whereas PCB74 males and offspring exposed to PCB95 were not affected. Pronounced changes were observed in BAEPs at low frequencies in PCB74 offspring, with elevated thresholds in both sexes. PCB95 increased thresholds in males, but not females. Small effects were detected on latency of the late wave IV in both sexes after developmental exposure to PCB74 or PCB95. Compared with the other NDL-PCB congeners tested, PCB74 caused the most pronounced effects on BAEPs.

Since knowledge about toxic effects of non-dioxinlike (NDL) PCBs is fragmentary, regulatory panels have concluded that risk assessment of these congeners is hampered or impossible. As the dopaminergic system is one of the main targets in PCB-related neurotoxic effects after developmental exposure, we selected catalepsy induced by the dopamine receptor blocker haloperidol to characterize effects of the NDL congeners PCB52 and PCB180 in adult offspring from exposed rat dams. Rat dams were treated with PCB congeners by gavage using six dose levels (total doses: PCB52 - 0, 30, 100, 300, 1000 or 3000 mg/kg body wt.; PCB180 - 0, 10, 30, 100, 300, or 1000 mg/kg body wt.) to allow benchmark dose analysis of the results. Testing of adult offspring (starting at 180 days of age) for catalepsy induced by injection with haloperidol revealed slightly prolonged latencies to movement onset in female offspring exposed to PCB52. Exposure to PCB180 resulted in more pronounced effects, with generally reduced latencies in male offspring. These results indicate reduced dopaminergic activity after PCB52 exposure, whereas the outcome for PCB180 may be related to increased extracellular dopamine as reported in the literature.Benchmark dose analyses revealed that both PCB congeners exerted effects mainly at moderate exposure levels. Together, these results underline the importance of effects on the dopaminergic system as indicated by studies in human females after occupational PCB exposure.

Many chemicals are known to exhibit endocrine activity and affect reproductive functions in vertebrates and invertebrates. Endocrine effects include influences on sexual differentiation of the brain during development and reproductive and non-reproductive behavior in adult offspring. We previously demonstrated that developmental exposure to a mixture of polychlorinated biphenyls (PCBs) which was reconstituted according to the congener pattern found in human breast milk caused feminization of sweet preference as a sexually dimorphic behavior in adult male rats, following decreases in aromatase activity in the brain of newborn male pups. This result may be due to dioxin-like or non-dioxin-like (NDL) PCBs and their respective effects on steroid hormones. The aim of the present experiments was to determine if exposure to highly purified NDL-PCBs (to remove Ah receptor active contaminants) also results in alteration of sweet preference. Pregnant rats were orally exposed to PCB52 (6 dose groups, total dose of 0-3000 mg/kg body weight) or PCB180 (6 dose groups, total dose of 0-1000 mg/kg body weight). In a further experiment rat dams were treated with equimolar doses of PCB74 or PCB95 (total dose, 760 mu mol/kg body weight, corresponding to 229 mg/kg or 248 mg/kg body weight of PCB74 and PCB95, respectively). Adult male and female offspring were given a choice between a bottle of saccharin solution (0.25%) and a bottle of tap water on five consecutive days. Control females consumed approximately twice as much sweetened solution compared with control males, thus, demonstrating sexual dimorphism of this behavior. Only non-significant reduction of sweet preference was found at the top dose level in female offspring after exposure to PCB52. Female offspring exposed to PCB180 exhibited signs of supernormal behavior as illustrated by increased saccharin consumption at intermediate dose levels. Decreased sweet preference was observed in females after developmental PCB74, whereas males were unaffected. Only PCB95 increased saccharin consumption in exposed males, leading to decreased sexual dimorphism of this behavior and behavioral feminization. The results demonstrate that different NDL-PCBs exhibit differential effects on sexually dimorphic behavior and that feminization occurs after removal of Ah receptor active contaminants. Comparison with data from the literature reveals little evidence for a relation to anti-androgenic activity of the studied NDL-PCBs. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

Background Polychlorinated biphenyls (PCBs) are a group of 209 congeners with similar basic structure, but differing in the number of chlorines and chlorination pattern. They are potent, persistent and accumulative, and abundantly present in food and the environment. A group of 12 congeners has a dioxin-like planar structure and toxicological properties similar to dioxins and are therefore called dioxin-like PCBs (DL-PCBs). Their risk assessment is included in that of other DL compounds. The rest of the PCBs, with nonplanar structure due to chlorine substitution at ortho position, have a different toxicological profile with possibly several different mechanisms. They are referred to as nondioxin-like PCBs (NDL-PCBs), and their toxic effects have been, so far, poorly characterized because of contamination of several used NDL-PCBs batches with very potent DL impurities (EFSA, 2005: http://www.efsa.europa.eu/de/ scdocs/doc/284.pdf). The aim of the ATHON (Assessing the Toxicity and Hazard of Non-dioxin-like PCBs Present in Food) project was to provide missing critical health hazard information, to clarify biological mechanisms underlying the various types of toxicity of NDL-PCBs and to evaluate these data from the risk assessment point-ofview.

Polychlorinated biphenyls (PCBs) are still present in the environment, with ongoing exposure in humans, including babies nursed by their mothers. Whereas toxicity of dioxin-like PCBs is well described, less systematic knowledge is available for non-dioxin like PCBs (NDL-PCBs) that do not act via the Ah receptor. This study compared effects of developmental exposure to two ultrapure NDL-PCB congeners (PCB52 and PCB180) on auditory function in rats, using the brainstem auditory evoked potential (BAEP). Pregnant rats received repeated oral doses of PCB52 (total dose-0, 30, 100, 300, 1000, or 3000 mg/kg body weight) or of PCB180 (total dose-0, 10, 30, 100, 300, or 1000 mg/kg). BAEPs were recorded in adult male and female offspring after stimulation with clicks or pure tones in the frequency range from 0.5 to 16 kHz. Significant elevation of BAEP thresholds was detected in the low-frequency range after developmental exposure to PCB52. Calculation of benchmark doses revealed lowest values in the frequency range of 0.5-2 kHz. Effects were more pronounced in male compared with female offspring. Latencies of waves II and IV were prolonged in exposed males, whereas only wave IV was affected in females. PCB180 increased thresholds only at few conditions and only in female offspring. These results confirm that developmental exposure to ultrapure NDL-PCBs affects auditory function, but different congeners exhibit differences in potencies.

Humans and animals are exposed to PCBs and influences on developmental and endocrine processes are among the most pronounced effects. In the present study it was hypothesised that exposure to PCBs may interfere with sexually dimorphic behaviour. To test this hypothesis, behavioural studies in developmentally exposed sheep were conducted. Ewes were orally administered PCB 153 (98 μg/kg bw day), PCB 118 (49 μg/kg bw day) or corn oil from conception until delivery. However, because of accidental cross-contamination occurring twice causing a mixed exposure scenario in all three groups, the focus of this paper is to compare three distinct groups of lambs with different PCB levels (PCB 153 high-PCB 153 h, PCB 118 high-PCB 118 h, and low combined group-LC) rather than comparing animals exposed to single PCB congeners to those of a control group. Lambs were tested between 2 and 6 weeks of age. When LC males started the light/dark choice test in a dark box, they spent significantly more time in the dark part of the pen than LC females. This gender-related difference was not found in groups exposed to PCBs. A significant inhibitory effect on the activity level of males exposed to stress of confinement was found in the PCB 118 h group. In a high stress situation females from PCB 118 h and males from PCB 153 h were less active than their gender counterparts. The results support the hypothesis that intrauterine exposure to PCBs can alter sexually dimorphic behaviour of offspring.

This overview summarizes neurotoxic effects of three different BFRs, polybrominated diphenyl ether (PBDE) 99, tetrabromobisphenol A (TBBPA), and hexabromocyclodocane (HBCD). The most prominent effect of PBDE 99 was feminization of sexually dimorphic behavior in male offspring after maternal exposure. Life-time exposure to TBBPA caused elevated thresholds in brainstem auditory evoked potentials (BAEPs) in female offspring and prolonged latencies of the late wave IV in both sexes. Alteration on a test of dopamine-dependent behavior was detected in HBCD exposed female offspring and elevated BAEP thresholds were found in exposed males. These results demonstrate that all three BFRs affect the nervous system, but they differ in their neurotoxic profiles.

This study is one of several baseline studies on commercially important Norwegian wild fish species that will provide information concerning metals and persistent organic pollutants (POPs) and food safety. The cod liver is a traditional food product in Norway and a potential source for POPs in the diet. The concentrations of dioxins and furans (PCDD/Fs), dioxin-like PCBs (DL-PCBs), non-dioxin-like PCBs (NDL-PCBs, PCB6) and polybrominated flame retardants (PBDEs) were determined in the liver of 784 individual Northeast Arctic cod caught at 32 positions in the Barents Sea in the period from 2009–2010. In addition, muscle samples from 30 individual cod were analysed for the same substances. The mean concentration of the sum of PCDD/Fs and DL-PCBs for all samples was 14.2 ng TEQwho-2005/kg ww with a variation between 1.0 and 151 ng TEQ/kg ww. The concentrations of POPs in the fillet samples were very low.

Home produced eggs from 62 addresses in the Netherlands were investigated for the levels of polychlorinated dibenzo-p-dioxins, dibenzofurans (PCDD/Fs) and biphenyls (PCBs), both dioxin-like (dl) and non-dioxin-like (ndl). Compared to commercial eggs, levels were relatively high with a median of 4.6 pg TEQ g−1 fat for the sum of PCDD/Fs and dl-PCBs, and a highest level of 18.9 pg TEQ g−1 fat. A number of samples showed clearly elevated ndl-PCB levels with a median of 13 ng g−1 fat and a highest level of 80 ng g−1 fat. There were no clear regional differences, even though part of the samples were derived from the rather industrial Rotterdam/Rijnmond area. Based on the congener patterns, former backyard burning of waste seems the most likely source for most eggs, with two exceptions where other sources contributed to the contamination. Similar is true for the ndl-PCBs. The study shows that average levels are about ten-fold higher than commercial eggs and may substantially contribute to the intake of PCDD/Fs and dl-PCBs by consumers. Intervention measures to reduce the intake of these contaminants by laying hens are advised.

The widespread use of brominated flame retardants (BFRs) has led to increasing concentrations in environmental samples. Previous reports suggested endocrine activity of these compounds. Because thyroid hormones and sex steroids are known to regulate the development of the nervous system, we examined neurobehavioral and endocrine effects of gestational exposure to 2,2'4,4',5-pentabrominated diphenyl ether (PBDE99) and lifetime exposure to tetrabromobisphenol A (TBBPA) or hexabromocyclododecane (HBCD) in rats. Treatment with PBDE99 (0, 1, or 10 mg/kg bw) reduced serum testosterone and estradiol in male offspring and affected sexual development in both sexes. Exposed males exhibited increased sweet preference, indicating feminization of this sexually dimorphic behavior. In TBBPA and HBCD experiments, a benchmark design was used with dose ranges of 03000 mg/kg bw/day and 0-100 mg/kg bw/day, respectively. Because thyroid hormones are critical for auditory development, brainstem auditory evoked potentials (BAEPs) were recorded in young adult offspring. TBBPA exposure elevated BAEP thresholds in females and prolonged latencies in both sexes. Benchmark doses were comparable for auditory effects and decreased plasma T4. HBCD increased BAEP thresholds and delayed BAEP waves only in males, but the relation to thyroid hormones remains to be determined. HBCD also reduced latencies in haloperidol-induced catalepsy, suggesting effects on the dopaminergic system.

Within the framework of an EU project on risk assessment of brominated flame retardants, TBBPA was studied for neurobehavioral effects in rats. To permit benchmark dose analysis, eight dose levels were chosen ranging from 0 to 3000mg/kg body weight. Exposure of parental rats started 10 and 2 weeks before mating in males and females, respectively, and was continued throughout mating, gestation and lactation. After weaning, exposure was continued in the offspring throughout life. Previous studies had indicated TBBPA-induced effects on thyroid hormones. Because of the known implication of thyroid hormones in neurodevelopment, the present experiments tested if TBBPA exposure affects thyroid-dependent neurobehavioral functions in offspring, such as auditory responses and conditioned fear. Sweet preference was included because of sex-specific effects in littermates. No statistically significant effects were found on context or cue conditioned fear or sweet preference. Auditory responses were examined with brainstem auditory evoked potentials (BAEPs) at approximately 50–110 days of age. BAEP thresholds and wave IV latency were increased in exposed female rats in the low frequency range. In male rats, thresholds were unaffected, but absolute latency of wave IV and interpeak latencies II–IV showed exposure-related increases at low frequencies. The outcome pattern suggests a predominant cochlear effect of TBBPA in females while in males neural effects are more apparent. According to benchmark analysis, the critical effect doses (CED) for prolongations of wave IV latency at 0.5kHz were in the range of 35–70mg/kg body weight with lower bounds (BMDL) of approximately 8mg/kg in males and females. The BMDL values for elevation of hearing thresholds in females were in the range of 1–40mg/kg body weight, depending on frequency. The benchmark doses for effects on the BAEP were similar to values for decreases in circulating thyroid hormones. The comparison of the exposure level at which the most sensitive effect was found with current human exposure levels yielded a margin of exposure of about 5, according to a recent risk assessment. Further investigations are needed to examine exposure pathways, fate in the body and effects of TBBPA.