Development of a Generic PBK Model for Human Biomonitoring with an Application to Deoxynivalenol.

Toxicokinetic modelling provides a powerful tool in relating internal human exposure (i.e., assessed through urinary biomarker levels) to external exposure. Chemical specific toxicokinetic models are available; however, this specificity prevents their application to similar contaminants or to other routes of exposure. For this reason, we investigated whether a generic physiological-based kinetic (PBK) model might be a suitable alternative for a biokinetic model of deoxynivalenol (DON). IndusChemFate (ICF) was selected as a generic PBK model, which could be fit for purpose. Being suited for simulating multiple routes of exposure, ICF has particularly been used to relate the inhalation and dermal exposure of industrial chemicals to their urinary excretion. For the first time, the ICF model was adapted as a generic model for the human biomonitoring of mycotoxins, thereby extending its applicability domain. For this purpose, chemical-specific data for DON and its metabolites were collected directly from the literature (distribution and metabolism) or indirectly (absorption and excretion) by fitting the ICF model to previously described urinary excretion data. The obtained results indicate that this generic model can be used to model the urinary excretion of DON and its glucuronidated metabolites following dietary exposure to DON. Additionally, the present study establishes the basis for further development of the model to include an inhalation exposure route alongside the oral exposure route.

New approach methodologies: A quantitative in vitro to in vivo extrapolation case study with PFASs.

PER: and polyfluoroalkyl substances (PFASs) have been associated with increased blood lipids in humans. Perfluorooctanoic acid (PFOA) has been also linked with elevated alanine transferase (ALT) serum levels in humans, and in rodents the liver is a main target organ for many PFASs. With the focus on New Approach Methodologies, the chronic oral equivalent effect doses were calculated for PFOA, PFNA (perfluorononanoic acid), PFHxS (perfluorohexanesulfonic acid) and PFOS (perfluorooctane sulfonic acid) based on in vitro effects measured in the HepaRG cell line. Selected in vitro readouts were considered biomarkers for lipid disturbances and hepatotoxicity. Concentration-response data obtained from HepaRG cells on triglyceride (TG) accumulation and expression changes of 12 selected genes (some involved in cholesterol homeostasis) were converted into corresponding human dose-response data, using physiologically based kinetic (PBK) model-facilitated reverse dosimetry. Next to this, the biokinetics of the chemicals were studied in the cell system. The current European dietary PFASs exposure overlaps with the calculated oral equivalent effect doses, indicating that the latter may lead to interference with hepatic gene expression and lipid metabolism. These findings illustrate an in vitro-in silico methodology, which can be applied for more PFASs, to select those that should be prioritized for further hazard characterization.

A congener-specific modelling approach for the transfer of polychlorinated dibenzo-p-dioxins and dibenzofurans and dioxin-like polychlorinated biphenyls from feed to eggs of laying hens.

Calibration of a kinetic model for the transfer of PCDD/Fs and dl-PCBs from feed to the hen's body and eggs was thus far restricted to the total TEQ concentration, i.e. the summed concentrations of PCDD/Fs and dl-PCBs expressed in terms of equivalents of 2,3,7,8-TCDD. However, this approach may lead to over- or underestimation of the transfer if the mixture contains congeners with kinetic characteristics which differ considerably from those used in such a model. This paper extends a previous transfer model of PCDD/Fs and dl-PCBs from feed to egg yolk fat and abdominal fat of high production laying hens, based on the total TEQ approach, to the level of individual congeners. Both modelling approaches are compared and the new approach is presented as a webtool application. This congener-specific approach enabled the calibration of 25 of the 29 relevant PCDD/F and dl-PCB congeners with respect to their individual transfer characteristics to body fat and egg yolk fat and their clearance from the body. Limitations of the available experimental data prevented the calibration of 1,2,3,4,6,7,8-HpCDD, OCDD, OCDF and PCB 123. The fraction transferred to egg yolk fat after long-term daily intake of contaminated feed was found to be at least 0.78 for 2,3,7,8-TCDD, 0.75 for PeCDD, 0.42-0.61 for HxCDDs, 0.70 for 2,3,7,8-TCDF, 0.71 for PeCDF, 0.54-0.60 for HxCDFs, 0.18-0.24 for HpCDFs and 0.89-1.00 for dl-PCBs. Various experimental and feed incident mixtures were used to compare the total TEQ- model with the congener-specific approach. An overestimation of the transfer by the total TEQ method was shown in particular for mixtures with a substantial contribution of hexa-, hepta- and octa-PCDD/Fs to the total TEQ level.

Applicability of generic PBK modelling in chemical hazard assessment: A case study with IndusChemFate.

Toxicology is moving away from animal testing towards in vitro tools to assess chemical safety. This new testing framework requires a quantitative method, i.e. kinetic modelling, which extrapolates effective concentrations in vitro to a bioequivalent human dose in vivo and which can be applied on "high throughput screening" of a wide variety of chemicals. Generic physiologically based kinetic (PBK) models help account for the role of toxicokinetics in setting human toxic exposure levels. Furthermore these models may be parameterized only on in silico QSARs and in vitro metabolism assays, thereby circumventing the use of in vivo toxicokinetics for this purpose. Though several such models exist their applicability domains have yet to be comprehensively assessed. This study extends previous evaluations of the PBK model IndusChemFate and compares it with its more complex biological complement ("TNO Model"). Both models were evaluated with a broad span of chemicals, varying regarding physicochemical properties. The results reveal that the "simpler" performed best, illustrating that IndusChemFate can be a useful first-tier for simulating toxicokinetics based on QSARs and in vitro parameters. Finally, proper quantitative in vitro to in vivo extrapolation conditions were illustrated starting with acetaminophen induced in vitro cytotoxicity in human HepaRG cells.

Internal Relative Potency Factors for the Risk Assessment of Mixtures of Per- and Polyfluoroalkyl Substances (PFAS) in Human Biomonitoring.

BACKGROUND: In human biomonitoring, blood is often used as a matrix to measure exposure to per- and polyfluoroalkyl substances (PFAS). Because the toxicokinetics of a substance (determining the steady-state blood concentration) may affect the toxic potency, the difference in toxicokinetics among PFAS has to be accounted for when blood concentrations are used in mixture risk assessment. OBJECTIVES: This research focuses on deriving relative potency factors (RPFs) at the blood serum level. These RPFs can be applied to PFAS concentrations in human blood, thereby facilitating mixture risk assessment with primary input from human biomonitoring studies. METHODS: Toxicokinetic models are generated for 10 PFAS to estimate the internal exposure in the male rat at the blood serum level over time. By applying dose-response modeling, these internal exposures are used to derive quantitative internal RPFs based on liver effects. RESULTS: Internal RPFs were successfully obtained for nine PFAS. Perfluorobutanoic acid (PFBA), perfluorohexanoic acid (PFHxA), perfluorononanoic acid (PFNA), perfluorododecanoic acid (PFDoDA), perfluorooctane sulfonic acid (PFOS), and hexafluoropropylene oxide-dimer acid (HFPO-DA, or GenX) were found to be more potent than perfluorooctanoic acid (PFOA) at the blood serum level in terms of relative liver weight increase, whereas perfluorobutane sulfonic acid (PFBS) and perfluorohexane sulfonic acid (PFHxS) were found to be less potent. The practical implementation of these internal RPFs is illustrated using the National Health and Nutrition Examination Survey (NHANES) biomonitoring data of 2017-2018. DISCUSSION: It is recommended to assess the health risk resulting from exposure to PFAS as combined, aggregate exposure to the extent feasible. https://doi.org/10.1289/EHP10009.

Integrating in vitro chemical transplacental passage into a generic PBK model: A QIVIVE approach.

With the increasing application of cell culture models as primary tools for predicting chemical safety, the quantitative extrapolation of the effective dose from in vitro to in vivo (QIVIVE) is of increasing importance. For developmental toxicity this requires scaling the in vitro observed dose-response characteristics to in vivo fetal exposure, while integrating maternal in vivo kinetics during pregnancy, in particular transplacental transfer. Here the transfer of substances across the placental barrier, has been studied using the in vitro BeWo cell assay and six embryotoxic compounds of different kinetic complexity. The BeWo assay results were incorporated in an existing generic Physiologically Based Kinetic (PBK) model which for this purpose was extended with rat pregnancy. Finally, as a "proof of principle", the BeWo PBK model was used to perform a QIVIVE based on developmental toxicity as observed in various different in vitro toxicity assays. The BeWo results illustrated different transport profiles of the chemicals across the BeWo monolayer, allocating the substances into two distinct groups: the 'quickly-transported' and the 'slowly-transported'. BeWo PBK exposure simulations during gestation were compared to experimentally measured maternal blood and fetal concentrations and a reverse dosimetry approach was applied to translate in vitro observed embryotoxicity into equivalent in vivo dose-response curves. This approach allowed for a direct comparison of the in vitro dose-response characteristics as observed in the Whole Embryo Culture (WEC), and the Embryonic Stem Cell test (cardiac:ESTc and neural:ESTn) with in vivo rat developmental toxicity data. Overall, the in vitro to in vivo comparisons suggest a promising future for the application of such QIVIVE methodologies for screening and prioritization purposes of developmental toxicants. Nevertheless, the clear need for further improvements is acknowledged for a wider application of the approach in chemical safety assessment.

Systemic PFOS and PFOA exposure and disturbed lipid homeostasis in humans: what do we know and what not?

Associations between per- and polyfluoroalkyl substances (PFASs) and increased blood lipids have been repeatedly observed in humans, but a causal relation has been debated. Rodent studies show reverse effects, i.e. decreased blood cholesterol and triglycerides, occurring however at PFAS serum levels at least 100-fold higher than those in humans. This paper aims to present the main issues regarding the modulation of lipid homeostasis by the two most common PFASs, PFOS and PFOA, with emphasis on the underlying mechanisms relevant for humans. Overall, the apparent contrast between human and animal data may be an artifact of dose, with different molecular pathways coming into play upon exposure to PFASs at very low versus high levels. Altogether, the interpretation of existing rodent data on PFOS/PFOA-induced lipid perturbations with respect to the human situation is complex. From a mechanistic perspective, research on human liver cells shows that PFOS/PFOA activate the PPARα pathway, whereas studies on the involvement of other nuclear receptors, like PXR, are less conclusive. Other data indicate that suppression of the nuclear receptor HNF4α signaling pathway, as well as perturbations of bile acid metabolism and transport might be important cellular events that require further investigation. Future studies with human-relevant test systems would help to obtain more insight into the mechanistic pathways pertinent for humans. These studies shall be designed with a careful consideration of appropriate dosing and toxicokinetics, so as to enable biologically plausible quantitative extrapolations. Such research will increase the understanding of possible perturbed lipid homeostasis related to PFOS/ PFOA exposure and the potential implications for human health.

Do background levels of the pesticide pirimiphosmethyl in plant-based aquafeeds affect food safety of farmed Atlantic salmon?

The substitution of fish oil and fishmeal with plant-based ingredients in commercial aquafeeds for Atlantic salmon, may introduce novel contaminants that have not previously been associated with farmed fish. The organophosphate pesticide pirimiphos-methyl (PM) is one of the novel contaminants that is most prevalent in commercial salmon feed. In this study, the feed-to-fillet transfer of dietary PM and its main metabolites was investigated in Atlantic salmon fillet. Based on the experimental determined PM and metabolite uptake, metabolisation, and elimination kinetics, a physiologically based toxicokinetic (PBTK) compartmental model was developed. Fish fed PM had a relatively low (~4%) PM retention and two main metabolites (2-DAMP and Desethyl-PM) were identified in liver, muscle, kidney and bile. The absence of more metabolised forms of 2-DAMP and Desethyl-PM in Atlantic salmon indicates different metabolism in cold-water fish compared to previous studies on ruminants. The model was used to simulate the long term (>1.5 years) feed-to-fillet transfer of PM + metabolite in Atlantic salmon under realistic farming conditions including seasonal fluctuations in feed intake, growth, and fat deposition in muscle tissue. The model predictions show that with the constant presence of the highest observed PM concentration in commercial salmon feed, fillet PM+ metabolite levels were approximately 5 nmol kg-1, with highest levels for the metabolite 2-DAMP. No EU maximum residue levels (MRL) for PM and its main metabolites exist in seafood to date, but the predicted levels were lower than the MRL for PM in swine of 32.7 nmol kg-1.

The Relationship Between Internal and External Dose: Some General Results Based on a Generic Compartmental Model.

Statements on how the internal-to-external-dose (IED) relationship looks like are often based on qualitative toxicokinetic arguments. For example, the recently proposed kinetically derived maximum dose (KMD) states that the IED relationship must have an inflection point, due to saturation of underlying processes like metabolism or absorption. However, such statements lack a solid quantitative foundation. Therefore, we derived expressions for the IED relationship for a number of scenarios based on a generic compartmental model involving saturation. The scenarios included repeated or single dose, and saturable metabolism or saturable absorption. For some of these scenarios, an explicit expression for the IED relationship can be derived, for others only implicit expressions can be established, which need to be evaluated numerically. The results show that saturable processes will lead to an IED relationship that is nonlinear over the whole dose range, ie, it can be approximated by a linear relationship at the lower end, whereas the approximation will become gradually poorer with increasing doses. The finding that saturation does not lead to an inflection point in the IED relationship, as assumed in the KMD, implies that the KMD is not a valid approach for selecting the top dose in toxicological studies. An additional use of our results is that the derived explicit expressions of the IED relationship can be fitted to IED data, and, possibly, for extrapolation outside the observed dose range.

Modelling the long-term feed-to-fillet transfer of leuco crystal violet and leuco malachite green in Atlantic salmon (Salmo salar).

Leuco crystal violet (LCV) and leuco malachite green (LMG) are the main metabolites of two dyes that are forbidden for use in food production, but can be present at low background concentration in novel Atlantic salmon feed ingredients such as processed animal proteins (animal by-product [ABP]). In this study, the potential transfer of dietary LCV or LMG to the fillet of farmed Atlantic salmon was investigated. The uptake and elimination rate kinetics were determined in seawater-adapted Atlantic salmon (initial weight 587 ± 148 g) fed two levels of either LCV- or LMG-enriched diets (~500 and 4000 µg kg-1, respectively) for 40 days, followed by a 90-day depuration period with feeding on control diets (<0.15 µg kg-1 LCV and LMG). A three-compartmental model was developed, based on a fillet fat, fillet muscle and a central body compartment comprising all other tissues. Model calibrations showed a good fit with measured values during overall uptake and elimination period; however, the model poorly predicted the short-term (days) peak measured values at the end of the exposure period. The model was used to simulate the long-term (>16 months) LCV and LMG feed-to-fillet transfer in Atlantic salmon under realistic farming conditions such as the seasonal fluctuations in feed intake, growth and fillet fat deposition. The model predictions gave highest expected LCV and LMG fillet concentrations of approximately 0.12 and 0.45 µg kg-1, depending on the dietary levels of ABP and background level of LCV and LMG contamination. These levels are under the reference point for action of 2 µg kg-1 for the sum of MG and LMG that EFSA assessed as adequate to protect public health. However, for LCV, the predicted highest levels exceed the analytical decision limit (CCα) of 0.15 µg kg-1 for the method used in this paper.

The importance of inclusion of kinetic information in the extrapolation of high-to-low concentrations for human limit setting.

Human health risk assessment of inhalation exposures generally includes a high-to-low concentration extrapolation. Although this is a common step in human risk assessment, it introduces various uncertainties. One of these uncertainties is related to the toxicokinetics. Many kinetic processes such as absorption, metabolism or excretion can be subject to saturation at high concentration levels. In the presence of saturable kinetic processes of the parent compound or metabolites, disproportionate increases in internal blood or tissue concentration relative to the external concentration administered may occur resulting in nonlinear kinetics. The present paper critically reviews human health risk assessment of inhalation exposure. More specific, it emphasizes the importance of kinetic information for the determination of a safe exposure in human risk assessment of inhalation exposures assessed by conversion from a high animal exposure to a low exposure in humans. For two selected chemicals, i.e. methyl tert-butyl ether and 1,2-dichloroethane, PBTK-modelling was used, for illustrative purposes, to follow the extrapolation and conversion steps as performed in existing risk assessments for these chemicals. Human health-based limit values based on an external dose metric without sufficient knowledge on kinetics might be too high to be sufficiently protective. Insight in the actual internal exposure, the toxic agent, the appropriate dose metric, and whether an effect is related to internal concentration or dose is important. Without this, application of assessment factors on an external dose metric and the conversion to continuous exposure results in an uncertain human health risk assessment of inhalation exposures.

In vitro to in vivo extrapolation of effective dosimetry in developmental toxicity testing: Application of a generic PBK modelling approach.

Incorporation of kinetics to quantitative in vitro to in vivo extrapolations (QIVIVE) is a key step for the realization of a non-animal testing paradigm, in the sphere of regulatory toxicology. The use of Physiologically-Based Kinetic (PBK) modelling for determining systemic doses of chemicals at the target site is accepted to be an indispensable element for such purposes. Nonetheless, PBK models are usually designed for a single or a group of compounds and are considered demanding, with respect to experimental data needed for model parameterization. Alternatively, we evaluate here the use of a more generic approach, i.e. the so-called IndusChemFate model, which is based on incorporated QSAR model parametrization. The model was used to simulate the in vivo kinetics of three diverse classes of developmental toxicants: triazoles, glycol ethers' alkoxyacetic acid metabolites and phthalate primary metabolites. The model required specific input per each class of compounds. These compounds were previously tested in three alternative assays: the whole-embryo culture (WEC), the zebrafish embryo test (ZET), and the mouse embryonic stem cell test (EST). Thereafter, the PBK-simulated blood levels at toxic in vivo doses were compared to the respective in vitro effective concentrations. Comparisons pertaining to relative potency and potency ranking with integration of kinetics were similar to previously obtained comparisons. Additionally, all three in vitro systems produced quite comparable results, and hence, a combination of alternative tests is still preferable for predicting the endpoint of developmental toxicity in vivo. This approach is put forward as biologically more plausible since plasma concentrations, rather than external administered doses, constitute the most direct in vivo dose metric.

Polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and biphenyls (PCBs) in home-produced eggs.

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.

Carry-over of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and polychlorinated biphenyls (PCBs) in dairy cows fed smoke contaminated maize silage or sugar beet pulp.

Fires and improper drying may result in contamination of feed with PCDD/Fs and PCBs. To predict the impact of elevated feed levels, it is important to understand the carry-over to edible products from food producing animals. Therefore, a carry-over study was performed with maize silage contaminated by a fire with PVC materials, and with sugar beet pulp contaminated by drying with coal, containing particles from a plastic roof. Levels of PCDD/Fs and dl-PCBs in the maize silage were 0.93 and 0.25 ng TEQ kg(-1), those in beet pulp 1.90 and 0.15 ng TEQ kg(-1) (both on 88% dry matter (DM)). Dairy cows (3 per treatment) received either 16.8 kg DM per day of maize silage or 5.6 kg DM per day of sugar beet pellets for a 33-d period, followed by clean feed for 33 days. This resulted in a rapid increase of PCDD/F levels in milk within the first 10 days with levels at day 33 of respectively 2.6 and 1.7 pg TEQ g(-1) fat for maize silage and beet pulp. Levels of dl-PCBs at day 33 were lower, 1.0 and 0.5 pg TEQ g(-1) fat. In the case of the maize silage, the carry-over rates (CORs) at the end of the exposure were calculated to be 25% and 32% for the PCDD/F- and dl-PCB-TEQ, respectively. For the dried beet pulp the CORs were 18% and 35%. This study shows that the carry-over of PCDD/Fs and dl-PCBs formed during drying processes or fires can be substantial.

Concentrations of dimethylaniline and other metabolites in milk and tissues of dairy cows treated with lidocaine.

Lidocaine is a topical anaesthetic drug used in dairy cows for laparotomy (caesarean section, abomasal displacement). Because there are no registered drugs for this indication, it can be applied under the so-called Cascade rules (off-label use), with the restriction that the off-label withdrawal periods of 7 days for milk and 28 days for meat are taken into account. In animals, lidocaine is rapidly metabolised into various metabolites, one being 2,6-dimethylaniline (DMA) which is reported to possess carcinogenic and mutagenic properties and detected also in milk. To investigate whether the off-label withdrawal periods are long enough to exclude the presence of lidocaine and DMA, and potential other metabolites, in edible products, a study was performed with eight dairy cows treated with lidocaine by injection in the abdominal muscles. At various time points blood samples, milk and urine were collected. Four animals were slaughtered 3.5 h after treatment, the other four after 48.5 h. The injection site, meat, liver and kidney were analysed for levels of lidocaine, DMA, monoethylglycinexylidide (MEGX) and 3-OH-lidocaine. It was shown that DMA is an important metabolite in dairy cows and can be detected in both meat and milk. In addition, also MEGX, 3-OH-lidocaine and three other metabolites were identified and to some extent quantified. These metabolites were 4-OH-lidocaine, lidocaine-N-oxide and 4-hydroxy-DMA. The latter compound was the most important metabolite in urine. However, levels in milk and meat decreased rapidly after the application. Overall, it can be concluded that the off-label withdrawal times of 7 and 28 days for milk and meat, respectively, guarantee the absence of detectable levels of lidocaine and metabolites.

Carryover of cadmium from feed in growing pigs.

Growing male pigs were exposed to cadmium (Cd) at levels around 1 and 10 mg kg(-1) feed for up to 12 weeks, administered as CdCl2 or Cd-cysteine (CdCys). Pigs exposed to 10 mg kg(-1) showed decreased growth during the last 3 weeks. Liver and kidney concentrations of Cd continuously increased over the entire 12-week exposure, exceeding the European Union limits of 1.0 mg kg(-1) (kidney) and 0.5 mg kg(-1) (liver) within 3 weeks at the feed level of 10 mg kg(-1). A switch to clean feed after 3 weeks for 5 or 9 weeks resulted in steadily decreased levels in kidney and liver, which could be completely attributed to organ growth. At the lower feed level, the level in kidney exceeded the limit almost twofold after 12 weeks, but not after 3 weeks. Liver levels remained below the limit. Metallothionein (MT) levels in livers showed a steady decrease in both untreated and treated animals over time. In kidney such a decrease was only observed in control animals, whereas in the highest-dosed animals the MT concentrations steadily increased. The observed carryover of Cd from feed to liver and kidney was modelled by means of a simple transfer model relating levels in feed via MT levels to accumulation of Cd. Using this model, it was shown that the exposure period of growing pigs to feed containing the European Union limit of 0.5 mg kg(-1) feed should be less than 12 weeks in order to prevent Cd levels in the kidneys to exceed the European Union limit.

Accumulation of polychlorinated dibenzo-p-dioxins, dibenzofurans, and biphenyls in livers of young sheep.

A major part of sheep livers contains levels of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and polychlorinated biphenyls (PCBs) above the former but to some extent also the new maximum levels (MLs) in the EU. In order to investigate the relationship between the intake of these contaminants and their accumulation in livers, kidney fat and meat, young blackhead sheep were fed with grass pellets containing PCDD/Fs at 2.5 times the maximum level. Levels of PCDD/Fs in livers were already quite high at the start of the exposure but increased 3-fold within 56d, exceeding the new product based MLs. Levels in meat and fat also increased but did not exceed the MLs. Although less elevated in the grass, both dl- and ndl-PCB levels also increased in liver and fat. Their kinetics in the tissues was less clear, potentially caused by increased levels in the straw given to the sheep during the whole experimental period. There was a clear difference in the behavior of the various congeners, the PCDFs and especially the higher chlorinated PCDFs and PCDDs showing a higher accumulation in the liver. In the case of the PCBs, this was particularly true for PCB 126. When switched to clean grass after 56d, the levels in livers and other tissues decreased to about the levels in the control sheep within 56d. This offers a potential solution for decreasing the intake of consumers.

Human risk assessment of dermal and inhalation exposures to chemicals assessed by route-to-route extrapolation: the necessity of kinetic data.

In toxicity testing the oral route is in general the first choice. Often, appropriate inhalation and dermal toxicity data are absent. Risk assessment for these latter routes usually has to rely on route-to-route extrapolation starting from oral toxicity data. Although it is generally recognized that the uncertainties involved are (too) large, route-to-route extrapolation is applied in many cases because of a strong need of an assessment of risks linked to a given exposure scenario. For an adequate route-to-route extrapolation the availability of at least some basic toxicokinetic data is a pre-requisite. These toxicokinetic data include all phases of kinetics, from absorption (both absorbed fraction and absorption rate for both the starting route and route of interest) via distribution and biotransformation to excretion. However, in practice only differences in absorption between the different routes are accounted for. The present paper demonstrates the necessity of route-specific absorption data by showing the impact of its absence on the uncertainty of the human health risk assessment using route-to-route extrapolation. Quantification of the absorption (by in vivo, in vitro or in silico methods), particularly for the starting route, is considered essential.

Fish consumption during child bearing age: a quantitative risk-benefit analysis on neurodevelopment.

The fish ingredient N3-docosahexaenoic acid 22:6 n-3 (DHA) stimulates brain development. On the other hand methylmercury (MeHg) in fish disturbs the developing central nervous system. In this Context the IQ score in children is considered as an aggregate measure of in utero brain development. To determine the effect of DHA exposure on prenatal neurodevelopment the maternal DHA intake during pregnancy was compared with its epidemiologically observed effect on the IQ score of children. For MeHg the maternal intake was converted into its accumulation in the maternal body. The maternal body burden then was compared with its epidemiologically observed relationship with the IQ score. Taking the MeHg and DHA content of 33 fish species the net effect of these compounds on the IQ score was quantified. For most fish species the adverse effect of MeHg on the IQ score exceeded the beneficial effect of DHA. In the case of long-living predators a negative effect up to 10 points on the IQ score was found. The results of this study indicate that food interventions aiming at the beneficial effects of fish consumption should focus on fish species with a high DHA content, while avoiding fish species with a high MeHg content.

Dioxins (polychlorinated dibenzo-p-dioxins and polychlorinated dibenzo-furans) in traditional clay products used during pregnancy.

Geophagy, the practice of consuming clay or soil, is encountered among pregnant women in Africa, Eastern Asia and Latin America, but also in Western societies. However, certain types of clay are known to contain high concentrations of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs). The aim of this study was to determine the PCDD/F contents of orally consumed clays purchased from Dutch and African markets. Congener patterns were compared with those of pooled human milk samples collected in eight African countries, to investigate a possible relationship with clay consumption. From the Dutch market thirteen clay products were examined, seven of African and six of Suriname origin. From seven African countries, twenty clay products were collected. All 33 clay products were screened with a cell-based bioassay and those showing a high response were analyzed by GC/HRMS. High PCDD/F concentrations were measured in three clay products from the Dutch market, ranging from 66 to 103 pg TEQ g(-1), whereas clay products from African countries were from 24 to 75 pg TEQ g(-1). Patterns and relatively high concentrations of PCDD/Fs in human milk samples from the Democratic Republic of the Congo and Côte d'Ivoire suggest a relationship with the consumption of contaminated clay. Frequent use of PCDD/F contaminated clay products during pregnancy may result in increased exposure of the mother and subsequently the developing fetus and new-born child. The use of these contaminated clays during pregnancy should be carefully considered or even discouraged.