• Acarological Risk of Borrelia burgdorferi Sensu Lato Infections Across Space and Time in The Netherlands.

      Takken, Willem; van Vliet, Arnold J H; Verhulst, Niels O; Jacobs, Frans H H; Gassner, Fedor; Hartemink, Nienke; Mulder, Sara; Sprong, Hein (2017)
      A longitudinal investigation on tick populations and their Borrelia infections in the Netherlands was undertaken between 2006 and 2011 with the aim to assess spatial and temporal patterns of the acarological risk in forested sites across the country and to assess variations in Borrelia genospecies diversity. Ticks were collected monthly in 11 sites and nymphs were examined for Borrelia infections. Tick populations expressed strong seasonal variations, with consistent and significant differences in mean tick densities between sites. Borrelia infections were present in all study sites, with a site-specific mean prevalence per month ranging from 7% to 26%. Prevalence was location-dependent and was not associated with tick densities. Mean Borrelia prevalence was lowest in January (4%), gradually increasing to reach a maximum (24%) in August. Borrelia afzelii represented 70% of all infections, with Borrelia burgdorferi sensu stricto, Borrelia garinii, and Borrelia valaisiana represented with 4%, 8%, and 10%, respectively. The density of infected nymphs and the proportional distribution of the four Borrelia genospecies, were significantly different between sites. The results show a consistent and significant spatial and temporal difference in acarological risk across the Netherlands.
    • Air Pollution from Livestock Farms Is Associated with Airway Obstruction in Neighboring Residents.

      Borlée, Floor; Yzermans, C Joris; Aalders, Bernadette; Rooijackers, Jos; Krop, Esmeralda; Maassen, Catharina B M; Schellevis, François; Brunekreef, Bert; Heederik, Dick; Smit, Lidwien A M (2017-11-01)
      Livestock farm emissions may not only affect respiratory health of farmers but also of neighboring residents.
    • Antimicrobial resistance at the interface of human and veterinary medicine.

      Köck, Robin; Kreienbrock, Lothar; van Duijkeren, Engeline; Schwarz, Stefan (2017-02)
    • APROBA-Plus: A probabilistic tool to evaluate and express uncertainty in hazard characterization and exposure assessment of substances.

      Bokkers, Bas G H; Mengelers, Marcel J; Bakker, Martine I; Chiu, Weihsueh A; Slob, Wout (2017-12)
      To facilitate the application of probabilistic risk assessment, the WHO released the APROBA tool. This tool applies lognormal uncertainty distributions to the different aspects of the hazard characterization, resulting in a probabilistic health-based guidance value. The current paper describes an extension, APROBA-Plus, which combines the output from the probabilistic hazard characterization with the probabilistic exposure to rapidly characterize risk and its uncertainty. The uncertainty in exposure is graphically compared with the uncertainty in the target human dose, i.e. the dose that complies with the specified protection goals. APROBA-Plus is applied to several case studies, resulting in distinct outcomes and illustrating that APROBA-Plus could serve as a standard extension of routine risk assessments. By visualizing the uncertainties, APROBA-Plus provides a more transparent and informative outcome than the more usual deterministic approaches, so that risk managers can make better informed decisions. For example, APROBA-Plus can help in deciding whether risk-reducing measures are warranted or that a refined risk assessment would first be needed. If the latter, the tool can be used to prioritize possible refinements. APROBA-Plus may also be used to rank substances into different risk categories, based on potential health risks without being compromised by different levels of conservatism that may be associated with point estimates of risk.
    • Attribution of global foodborne disease to specific foods: Findings from a World Health Organization structured expert elicitation.

      Hoffmann, Sandra; Devleesschauwer, Brecht; Aspinall, Willy; Cooke, Roger; Corrigan, Tim; Havelaar, Arie; Angulo, Frederick; Gibb, Herman; Kirk, Martyn; Lake, Robin; et al. (2017)
      Recently the World Health Organization, Foodborne Disease Burden Epidemiology Reference Group (FERG) estimated that 31 foodborne diseases (FBDs) resulted in over 600 million illnesses and 420,000 deaths worldwide in 2010. Knowing the relative role importance of different foods as exposure routes for key hazards is critical to preventing illness. This study reports the findings of a structured expert elicitation providing globally comparable food source attribution estimates for 11 major FBDs in each of 14 world subregions.
    • Changes in LXR signaling influence early-pregnancy lipogenesis and protect against dysregulated fetoplacental lipid homeostasis.

      Nikolova, Vanya; Papacleovoulou, Georgia; Bellafante, Elena; Borges Manna, Luiza; Jansen, Eugene; Baron, Silvère; Abu-Hayyeh, Shadi; Parker, Malcolm; Williamson, Catherine (2017-10-01)
      Human pregnancy is associated with enhanced de novo lipogenesis in the early stages followed by hyperlipidemia during advanced gestation. Liver X receptors (LXRs) are oxysterol-activated nuclear receptors that stimulate de novo lipogenesis and also promote the efflux of cholesterol from extrahepatic tissues followed by its transport back to the liver for biliary excretion. Although LXR is recognized as a master regulator of triglyceride and cholesterol homeostasis, it is unknown whether it facilitates the gestational adaptations in lipid metabolism. To address this question, biochemical profiling, protein quantification, and gene expression studies were used, and gestational metabolic changes in T0901317-treated wild-type mice and Lxrab-/- mutants were investigated. Here, we show that altered LXR signaling contributes to the enhanced lipogenesis in early pregnancy by increasing the expression of hepatic Fas and stearoyl-CoA desaturase 1 (Scd1). Both the pharmacological activation of LXR with T0901317 and the genetic ablation of its two isoforms disrupted the increase in hepatic fatty acid biosynthesis and the development of hypertriglyceridemia during early gestation. We also demonstrate that absence of LXR enhances maternal white adipose tissue lipolysis, causing abnormal accumulation of triglycerides, cholesterol, and free fatty acids in the fetal liver. Together, these data identify LXR as an important factor in early-pregnancy lipogenesis that is also necessary to protect against abnormalities in fetoplacental lipid homeostasis.
    • Comparative Genome Analysis and Global Phylogeny of the Toxin Variant Clostridium difficile PCR Ribotype 017 Reveals the Evolution of Two Independent Sublineages.

      Cairns, M D; Preston, M D; Hall, C L; Gerding, D N; Hawkey, P M; Kato, H; Kim, H; Kuijper, E J; Lawley, T D; Pituch, H; et al. (2017)
      The diarrheal pathogen Clostridium difficile consists of at least six distinct evolutionary lineages. The RT017 lineage is anomalous, as strains only express toxin B, compared to strains from other lineages that produce toxins A and B and, occasionally, binary toxin. Historically, RT017 initially was reported in Asia but now has been reported worldwide. We used whole-genome sequencing and phylogenetic analysis to investigate the patterns of global spread and population structure of 277 RT017 isolates from animal and human origins from six continents, isolated between 1990 and 2013. We reveal two distinct evenly split sublineages (SL1 and SL2) of C. difficile RT017 that contain multiple independent clonal expansions. All 24 animal isolates were contained within SL1 along with human isolates, suggesting potential transmission between animals and humans. Genetic analyses revealed an overrepresentation of antibiotic resistance genes. Phylogeographic analyses show a North American origin for RT017, as has been found for the recently emerged epidemic RT027 lineage. Despite having only one toxin, RT017 strains have evolved in parallel from at least two independent sources and can readily transmit between continents.
    • Comparing BMD-derived genotoxic potency estimations across variants of the transgenic rodent gene mutation assay.

      Wills, John W; Johnson, George E; Battaion, Hannah L; Slob, Wout; White, Paul A (2017)
      There is growing interest in quantitative analysis of in vivo genetic toxicity dose-response data, and use of point-of-departure (PoD) metrics such as the benchmark dose (BMD) for human health risk assessment (HHRA). Currently, multiple transgenic rodent (TGR) assay variants, employing different rodent strains and reporter transgenes, are used for the assessment of chemically-induced genotoxic effects in vivo. However, regulatory issues arise when different PoD values (e.g., lower BMD confidence intervals or BMDLs) are obtained for the same compound across different TGR assay variants. This study therefore employed the BMD approach to examine the ability of different TGR variants to yield comparable genotoxic potency estimates. Review of over 2000 dose-response datasets identified suitably-matched dose-response data for three compounds (ethyl methanesulfonate or EMS, N-ethyl-N-nitrosourea or ENU, and dimethylnitrosamine or DMN) across four commonly-used murine TGR variants (Muta™Mouse lacZ, Muta™Mouse cII, gpt delta and BigBlue® lacI). Dose-response analyses provided no conclusive evidence that TGR variant choice significantly influences the derived genotoxic potency estimate. This conclusion was reliant upon taking into account the importance of comparing BMD confidence intervals as opposed to directly comparing PoD values (e.g., comparing BMDLs). Comparisons with earlier works suggested that with respect to potency determination, tissue choice is potentially more important than choice of TGR assay variant. Scoring multiple tissues selected on the basis of supporting toxicokinetic information is therefore recommended. Finally, we used typical within-group variances to estimate preliminary endpoint-specific benchmark response (BMR) values across several TGR variants/tissues. We discuss why such values are required for routine use of genetic toxicity PoDs for HHRA. Environ. Mol. Mutagen. 58:632-643, 2017. © 2017 Her Majesty the Queen in Right of Canada. Environmental and Molecular Mutagenesis Published by Wiley Periodicals, Inc.
    • Consumption of Fish Is Not Associated with Risk of Differentiated Thyroid Carcinoma in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study.

      Zamora-Ros, Raul; Castañeda, Jazmín; Rinaldi, Sabina; Cayssials, Valerie; Slimani, Nadia; Weiderpass, Elisabete; Tsilidis, Konstantinos K; Boutron-Ruault, Marie-Christine; Overvad, Kim; Eriksen, Anne K; et al. (2017)
      Background: Differentiated thyroid cancer (TC) is the most common endocrine cancer. Fish can be an important source of iodine and other micronutrients and contaminants that may affect the thyroid gland and TC risk.Objective: We prospectively evaluated the relations between the consumption of total fish and different fish types and shellfish and TC risk in the EPIC (European Prospective Investigation into Cancer and Nutrition) study.Methods: EPIC is a cohort of >500,000 men and women, mostly aged 35-70 y, who were recruited in 10 European countries. After a mean follow-up of 14 y, 748 primary differentiated TC cases were diagnosed; 666 were in women and 601 were papillary TC. Data on intakes of lean fish, fatty fish, fish products, and shellfish were collected by using country-specific validated dietary questionnaires at recruitment. Multivariable Cox regression was used to calculate HRs and 95% CIs adjusted for many potential confounders, including dietary and nondietary factors.Results: No significant association was observed between total fish consumption and differentiated TC risk for the highest compared with the lowest quartile (HR: 1.03; 95% CI: 0.81, 1.32; P-trend = 0.67). Likewise, no significant association was observed with the intake of any specific type of fish, fish product, or shellfish. No significant heterogeneity was found by TC subtype (papillary or follicular tumors), by sex, or between countries with low and high TC incidence.Conclusion: This large study shows that the intake of fish and shellfish was not associated with differentiated TC risk in Europe, a region in which iodine deficiency or excess is rare.
    • Coxiella burnetii (Q fever) prevalence in associated populations of humans and small ruminants in The Gambia.

      Bok, Jeroen; Hogerwerf, Lenny; Germeraad, Eveline A; Roest, Hendrik I J; Faye-Joof, Tisbeh; Jeng, Momodou; Nwakanma, Davis; Secka, Arss; Stegeman, Arjan; Goossens, Bart; et al. (2017)
      To simultaneously estimate the prevalence of antibodies against Coxiella burnetii (Q fever) among adults and small ruminants, and C. burnetii shedding prevalence among small ruminants in households in the Kiang West district of The Gambia, and to assess associated risk factors.
    • Dietary restriction but not angiotensin II type 1 receptor blockade improves DNA damage-related vasodilator dysfunction in rapidly aging Ercc1Δ/- mice.

      Wu, Haiyan; van Thiel, Bibi S; Bautista-Niño, Paula K; Reiling, Erwin; Durik, Matej; Leijten, Frank P J; Ridwan, Yanto; Brandt, Renata M C; van Steeg, Harry; Dollé, Martijn E T; et al. (2017-08-01)
      DNA damage is an important contributor to endothelial dysfunction and age-related vascular disease. Recently, we demonstrated in a DNA repair-deficient, prematurely aging mouse model (Ercc1Δ/- mice) that dietary restriction (DR) strongly increases life- and health span, including ameliorating endothelial dysfunction, by preserving genomic integrity. In this mouse mutant displaying prominent accelerated, age-dependent endothelial dysfunction we investigated the signaling pathways involved in improved endothelium-mediated vasodilation by DR, and explore the potential role of the renin-angiotensin system (RAS). Ercc1Δ/- mice showed increased blood pressure and decreased aortic relaxations to acetylcholine (ACh) in organ bath experiments. Nitric oxide (NO) signaling and phospho-Ser1177-eNOS were compromised in Ercc1Δ/- DR improved relaxations by increasing prostaglandin-mediated responses. Increase of cyclo-oxygenase 2 and decrease of phosphodiesterase 4B were identified as potential mechanisms. DR also prevented loss of NO signaling in vascular smooth muscle cells and normalized angiotensin II (Ang II) vasoconstrictions, which were increased in Ercc1Δ/- mice. Ercc1Δ/- mutants showed a loss of Ang II type 2 receptor-mediated counter-regulation of Ang II type 1 receptor-induced vasoconstrictions. Chronic losartan treatment effectively decreased blood pressure, but did not improve endothelium-dependent relaxations. This result might relate to the aging-associated loss of treatment efficacy of RAS blockade with respect to endothelial function improvement. In summary, DR effectively prevents endothelium-dependent vasodilator dysfunction by augmenting prostaglandin-mediated responses, whereas chronic Ang II type 1 receptor blockade is ineffective.
    • The effect of zirconium doping of cerium dioxide nanoparticles on pulmonary and cardiovascular toxicity and biodistribution in mice after inhalation.

      Dekkers, Susan; Miller, Mark R; Schins, Roel P F; Römer, Isabella; Russ, Mike; Vandebriel, Rob J; Lynch, Iseult; Belinga-Desaunay, Marie-France; Valsami-Jones, Eugenia; Connell, Shea P; et al. (2017-08)
      Development and manufacture of nanomaterials is growing at an exponential rate, despite an incomplete understanding of how their physicochemical characteristics affect their potential toxicity. Redox activity has been suggested to be an important physicochemical property of nanomaterials to predict their biological activity. This study assessed the influence of redox activity by modification of cerium dioxide nanoparticles (CeO2 NPs) via zirconium (Zr) doping on the biodistribution, pulmonary and cardiovascular effects in mice following inhalation. Healthy mice (C57BL/6 J), mice prone to cardiovascular disease (ApoE-/-, western-diet fed) and a mouse model of neurological disease (5 × FAD) were exposed via nose-only inhalation to CeO2 NPs with varying amounts of Zr-doping (0%, 27% or 78% Zr), or clean air, over a four-week period (4 mg/m3 for 3 h/day, 5 days/week). Effects were assessed four weeks post-exposure. In all three mouse models CeO2 NP exposure had no major toxicological effects apart from some modest inflammatory histopathology in the lung, which was not related to the amount of Zr-doping. In ApoE-/- mice CeO2 did not change the size of atherosclerotic plaques, but there was a trend towards increased inflammatory cell content in relation to the Zr content of the CeO2 NPs. These findings show that subacute inhalation of CeO2 NPs causes minimal pulmonary and cardiovascular effect four weeks post-exposure and that Zr-doping of CeO2 NPs has limited effect on these responses. Further studies with nanomaterials with a higher inherent toxicity or a broader range of redox activities are needed to fully assess the influence of redox activity on the toxicity of nanomaterials.
    • Exploring uptake and biodistribution of polystyrene (nano)particles in zebrafish embryos at different developmental stages.

      van Pomeren, M; Brun, N R; Peijnenburg, W J G M; Vijver, M G (2017-09)
      In ecotoxicology, it is continuously questioned whether (nano)particle exposure results in particle uptake and subsequent biodistribution or if particles adsorb to the epithelial layer only. To contribute to answering this question, we investigated different uptake routes in zebrafish embryos and how they affect particle uptake into organs and within whole organisms. This is addressed by exposing three different life stages of the zebrafish embryo in order to cover the following exposure routes: via chorion and dermal exposure; dermal exposure; oral and dermal exposure. How different nanoparticle sizes affect uptake routes was assessed by using polystyrene particles of 25, 50, 250 and 700nm. In our experimental study, we showed that particle uptake in biota is restricted to oral exposure, whereas the dermal route resulted in adsorption to the epidermis and gills only. Ingestion followed by biodistribution was observed for the tested particles of 25 and 50nm. The particles spread through the body and eventually accumulated in specific organs and tissues such as the eyes. Particles larger than 50nm were predominantly adsorbed onto the intestinal tract and outer epidermis of zebrafish embryos. Embryos exposed to particles via both epidermis and intestine showed highest uptake and eventually accumulated particles in the eye, whereas uptake of particles via the chorion and epidermis resulted in marginal uptake. Organ uptake and internal distribution should be monitored more closely to provide more in depth information of the toxicity of particles.
    • The first isolation and molecular characterization of Toxoplasma gondii from horses in Serbia.

      Klun, Ivana; Uzelac, Aleksandra; Villena, Isabelle; Mercier, Aurélien; Bobić, Branko; Nikolić, Aleksandra; Rajnpreht, Irena; Opsteegh, Marieke; Aubert, Dominique; Blaga, Radu; et al. (2017-04-04)
      Consumption of undercooked or insufficiently cured meat is a major risk factor for human infection with Toxoplasma gondii. Although horsemeat is typically consumed rare or undercooked, information on the risk of T. gondii from infected horse meat to humans is scarce. Here, we present the results of a study to determine the presence of T. gondii infection in slaughter horses in Serbia, and to attempt to isolate viable parasites.
    • Fish embryo toxicity test, threshold approach, and moribund as approaches to implement 3R principles to the acute fish toxicity test.

      Dang, ZhiChao; van der Ven, Leo T M; Kienhuis, Anne S (2017-11)
      The acute fish toxicity test (AFT) is requested by EU legal frameworks for hazard classification and risk assessment. AFT is one of the few regulatory required tests using death as an endpoint. This paper reviews efforts made to reduce, refine and replace (3Rs) AFT. We make an inventory of information requirements for AFT, summarize studies on 3Rs of AFT and give recommendations. The fish embryo toxicity test (FET) is proposed as a replacement of AFT and analyses have focused on two aspects: assessing the capacity of FET in predicting AFT and defining the applicability domain of FET. Six comparison studies have consistently shown a strong correlation of FET and AFT. In contrast, the applicability domain of FET has not yet been fully defined. FET has not yet been accepted as a replacement of AFT by any EU legal frameworks to fulfill information requirements because FET is insensitive to some chemicals. It is recommended that the outlier chemicals that do not correlate between FET and AFT should be further investigated. When necessary, additional FET data should be generated. Another effort to reduce and refine AFT is incorporation of FET into the threshold approach. Furthermore, moribund as an endpoint of fish death has been introduced in revising AFT guideline to reduce the duration of suffering for refinement. This endpoint, however, needs further work on the link of moribund and death. Global regulatory acceptance of the moribund endpoint would be critical for this development.
    • Heterosubtypic cross-reactivity of HA1 antibodies to influenza A, with emphasis on nonhuman subtypes (H5N1, H7N7, H9N2).

      Te Beest, Dennis E; de Bruin, Erwin; Imholz, Sandra; Koopmans, Marion; van Boven, Michiel (2017)
      Epidemics of influenza A vary greatly in size and age distribution of cases, and this variation is attributed to varying levels of pre-existing immunity. Recent studies have shown that antibody-mediated immune responses are more cross-reactive than previously believed, and shape patterns of humoral immunity to influenza A viruses over long periods. Here we quantify antibody responses to the hemagglutinin subunit 1 (HA1) across a range of subtypes using protein microarray analysis of cross-sectional serological surveys carried out in the Netherlands before and after the A/2009 (H1N1) pandemic. We find significant associations of responses, both within and between subtypes. Interestingly, substantial overall reactivity is observed to HA1 of avian H7N7 and H9N2 viruses. Seroprevalence of H7N7 correlates with antibody titers to A/1968 (H3N2), and is highest in persons born between 1954 and 1969. Seroprevalence of H9N2 is high across all ages, and correlates strongly with A/1957 (H2N2). This correlation is most pronounced in A/2009 (H1N1) infected persons born after 1968 who have never encountered A/1957 (H2N2)-like viruses. We conclude that heterosubtypic antibody cross-reactivity, both between human subtypes and between human and nonhuman subtypes, is common in the human population.
    • How Adverse Outcome Pathways Can Aid the Development and Use of Computational Prediction Models for Regulatory Toxicology.

      Wittwehr, Clemens; Aladjov, Hristo; Ankley, Gerald; Byrne, Hugh J; de Knecht, Joop; Heinzle, Elmar; Klambauer, Günter; Landesmann, Brigitte; Luijten, Mirjam; MacKay, Cameron; et al. (2017-02)
      Efforts are underway to transform regulatory toxicology and chemical safety assessment from a largely empirical science based on direct observation of apical toxicity outcomes in whole organism toxicity tests to a predictive one in which outcomes and risk are inferred from accumulated mechanistic understanding. The adverse outcome pathway (AOP) framework provides a systematic approach for organizing knowledge that may support such inference. Likewise, computational models of biological systems at various scales provide another means and platform to integrate current biological understanding to facilitate inference and extrapolation. We argue that the systematic organization of knowledge into AOP frameworks can inform and help direct the design and development of computational prediction models that can further enhance the utility of mechanistic and in silico data for chemical safety assessment. This concept was explored as part of a workshop on AOP-Informed Predictive Modeling Approaches for Regulatory Toxicology held September 24-25, 2015. Examples of AOP-informed model development and its application to the assessment of chemicals for skin sensitization and multiple modes of endocrine disruption are provided. The role of problem formulation, not only as a critical phase of risk assessment, but also as guide for both AOP and complementary model development is described. Finally, a proposal for actively engaging the modeling community in AOP-informed computational model development is made. The contents serve as a vision for how AOPs can be leveraged to facilitate development of computational prediction models needed to support the next generation of chemical safety assessment.
    • How radiation influences atherosclerotic plaque development: a biophysical approach in ApoE[Formula: see text] mice.

      Kloosterman, Astrid; Dillen, Teun van; Bijwaard, Harmen; Heeneman, Sylvia; Hoving, Saske; Stewart, Fiona A; Dekkers, Fieke (2017)
      Atherosclerosis is the development of lipid-laden plaques in arteries and is nowadays considered as an inflammatory disease. It has been shown that high doses of ionizing radiation, as used in radiotherapy, can increase the risk of development or progression of atherosclerosis. To elucidate the effects of radiation on atherosclerosis, we propose a mathematical model to describe radiation-promoted plaque development. This model distinguishes itself from other models by combining plaque initiation and plaque growth, and by incorporating information from biological experiments. It is based on two consecutive processes: a probabilistic dose-dependent plaque initiation process, followed by deterministic plaque growth. As a proof of principle, experimental plaque size data from carotid arteries from irradiated ApoE[Formula: see text] mice was used to illustrate how this model can provide insight into the underlying biological processes. This analysis supports the promoting role for radiation in plaque initiation, but the model can easily be extended to include dose-related effects on plaque growth if available experimental data would point in that direction. Moreover, the model could assist in designing future biological experiments on this research topic. Additional biological data such as plaque size data from chronically-irradiated mice or experimental data sets with a larger variety in biological parameters can help to further unravel the influence of radiation on plaque development. To the authors' knowledge, this is the first biophysical model that combines probabilistic and mechanistic modeling which uses experimental data to investigate the influence of radiation on plaque development.
    • Implementing wildlife disease surveillance in the Netherlands, a One Health approach.

      Maas, M; Gröne, A; Kuiken, T; Van Schaik, G; Roest, H I J; Van Der Giessen, J W B (2016-12)
      The surveillance of (emerging) wildlife diseases can provide important, objective evidence of the circulation of pathogens of interest for veterinary and/or public health. The involvement of multiple research institutions in wildlife disease surveillance can ensure the best use of existing knowledge and expertise, but can also complicate or add challenges to the integration of wildlife disease surveillance components into a national programme. Documenting the existing efforts in a country's surveillance of wildlife diseases, including the institutes in which it takes place, provides a basis for policy-makers and authorities to identify gaps and priorities in their current surveillance programmes. This paper describes the wildlife disease surveillance activities taking place in the Netherlands. The authors recommend that, in addition to funding these current activities, surveillance resources should be allocated with the flexibility to allow for additional targeted surveillance, to detect and adequately respond to newly introduced or emerging pathogens. Similar structured overviews of wildlife disease surveillance in other countries would be very useful to facilitate international collaboration.
    • The importance of inclusion of kinetic information in the extrapolation of high-to-low concentrations for human limit setting.

      Geraets, Liesbeth; Zeilmaker, Marco J; Bos, Peter M J (2018-01-05)
      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.