Immunosuppression, oxidative stress, and apoptosis in pig kidney caused by ammonia: Application of transcriptome analysis in risk assessment of ammonia exposure.

Ammonia (NH3) is a recognized environmental contaminant around the world and has adverse effects on animal and human health. However, the mechanism of the renal toxicity of NH3 is not well understood. Pigs are considered an ideal model for biomedical and toxicological research because of the similarity to humans in physiological and biochemical basis. Therefore, in this study, twelve pigs were selected as research objects and randomly divided into two groups, namely the control group and the NH3 group. The formal experiment lasted 30 days. The effects of excessive NH3 inhalation on the kidney of fattening pig were evaluated by chemical analysis, ELISA, transcriptome analysis and real-time quantitative PCR (qRT-PCR) from the renal antioxidant level, renal function, blood ammonia content and gene level. Our results showed that excessive NH3 exposure could cause an increase in blood NH3 content, a reduction in renal GSH-Px, SOD and GSH, as well as an increase in MDA levels and an increase in serum creatinine, urea and uric acid levels. In addition, transcriptome analysis showed that NH3 exposure caused changes in 335 differentially expressed genes (DEGs) (including 126 up-regulated DEGs and 109 down-regulated DEGs). Some highly expressed DEGs were enriched into GO terms associated with immune function, oxidative stress, and apoptosis and were verified by qRT-PCR. The qRT-PCR results were comsistent with the transcriptome results. Our results indicated that NH3 exposure could cause changes in renal transcriptional profiles and kidney function, and induce kidney damage in the fattening pigs through oxidative stress, immune dysfunction and apoptosis. Our present study provides novel insights into the immunotoxicity mechanism of NH3 on kidney.

Dietary Intake of Essential, Toxic, and Potentially Toxic Elements from Mussels (Mytilus spp.) in the Spanish Population: A Nutritional Assessment.

The levels of forty-three elements were determined in fresh, preserved, and frozen mussels (n = 208) with the purpose of evaluating their contribution to the recommended dietary intake of essential elements and their potential risk to Spanish consumers' health. We found relevant differences in the element content in relation to the mode of conservation of mussels as well as in relation to their geographical origin, brand, or mode of production. According to our estimates, mussels are important contributors to the intake of most essential elements, contributing almost 70% of daily requirements of Se, 30-35% of Mo, Zn, and Co, and around 15% of Fe. At the same time, the pattern of average consumption of mussels in Spain does not seem to imply an excessive risk associated with any of the 36 toxic elements studied. However, it should be noted that, in the high percentile of consumption the exposure to Cd and As may be high, in particular that associated with the consumption of fresh and/or frozen mussels. According to the results of this study, a moderate consumption of mussels can be recommended as a valuable and safe source of trace elements.

Incorporation of the glutathione conjugation pathway in an updated physiologically-based pharmacokinetic model for perchloroethylene in mice.

BACKGROUND: Perchloroethylene (perc) induced target organ toxicity has been associated with tissue-specific metabolic pathways. Previous physiologically-based pharmacokinetic (PBPK) modeling of perc accurately predicted oxidative metabolites but suggested the need to better characterize glutathione (GSH) conjugation as well as toxicokinetic uncertainty and variability. OBJECTIVES: We updated the previously published "harmonized" perc PBPK model in mice to better characterize GSH conjugation metabolism as well as the uncertainty and variability of perc toxicokinetics. METHODS: The updated PBPK model includes expanded models for perc and its oxidative metabolite trichloroacetic acid (TCA), and physiologically-based sub-models for conjugative metabolites. Previously compiled mouse kinetic data in B6C3F1 and Swiss-Webster mice were augmented to include data from a recent study in male C57BL/6J mice that measured perc and metabolites in serum and multiple tissues. Hierarchical Bayesian population analysis using Markov chain Monte Carlo was conducted to characterize uncertainty and inter-strain variability in perc metabolism. RESULTS: The updated model fit the data as well or better than the previously published "harmonized" PBPK model. Tissue dosimetry for both oxidative and conjugative metabolites was successfully predicted across the three strains of mice, with estimated residuals errors of 2-fold for majority of data. Inter-strain variability across three strains was evident for oxidative metabolism; GSH conjugation data were only available for one strain. CONCLUSIONS: This updated PBPK model fills a critical data gap in quantitative risk assessment by predicting the internal dosimetry of perc and its oxidative and GSH conjugation metabolites and lays the groundwork for future studies to better characterize toxicokinetic variability.

A global human health risk assessment for octamethylcyclotetrasiloxane (D4).

Octamethylcyclotetrasiloxane (D4) is a low-molecular-weight volatile cyclic siloxane, primarily used as an intermediate in the production of some widely-used industrial and consumer silicone based polymers and may be present as a component in a variety of consumer products. A global "harmonized" risk assessment was conducted to meet requirements for substance-specific risk assessments conducted by regulatory agencies such as USEPA's Integrated Risk Information System (IRIS), Health Canada's Chemical Management Program (CMP) and various independent scientific committees of the European Commission (e.g. the Scientific Committee on Consumer Safety (SCCS), the Scientific Committee on Health and Environmental Risks (SCHER)), as well as to provide guidance for chemical safety assessments under REACH in Europe. This risk assessment incorporates global exposure information combined with a Monte Carlo analysis to determine the most significant routes of exposure. Utilization of a multi-species, multi-route physiologically based pharmacokinetic (PBPK) model was included to estimate internal dose metrics, benchmark modeling was used to determine a point of departure (POD), and a margin of safety (MOS) evaluation was used to compare the estimates of intake with the POD. Because of the specific pharmacokinetic behaviors of D4 including high lipophilicity, high volatility with low blood-to-air partition coefficients and an extensive metabolic clearance that regulates tissue dose after exposure, the use of a PBPK model was essential to provide a comparison of a dose metric that reflects these processes. The characterization of the potential for adverse effects after exposure to D4 using a MOS approach based on an internal dose metric removes the subjective application of varying uncertainty factors from various regulatory agencies and allows examination of the differences between internal dose metrics associated with exposure and those associated with adverse effects.

Risk assessment strategies for nanoscale and fine-sized titanium dioxide particles: Recognizing hazard and exposure issues.

The basic tenets for assessing health risks posed by nanoparticles (NP) requires documentation of hazards and the corresponding exposures that may occur. Accordingly, this review describes the range and types of potential human exposures that may result from interactions with titanium dioxide (TiO2) particles or NP - either in the occupational/workplace environment, or in consumer products, including food materials and cosmetics. Each of those applications has a predominant route of exposure. Very little is known about the human impact potential from environmental exposures to NP - thus this particular issue will not be discussed further. In the workplace or occupational setting inhalation exposure predominates. Experimental toxicity studies demonstrate low hazards in particle-exposed rats. Only at chronic overload exposures do rats develop forms of lung pathology. These findings are not supported by multiple epidemiology studies in heavily-exposed TiO2 workers which demonstrate a lack of correlation between chronic particle exposures and adverse health outcomes including lung cancer and noncancerous chronic respiratory effects. Cosmetics and sunscreens represent the major application of dermal exposures to TiO2 particles. Experimental dermal studies indicate a lack of penetration of particles beyond the epidermis with no consequent health risks. Oral exposures to ingested TiO2 particles in food occur via passage through the gastrointestinal tract (GIT), with studies indicating negligible uptake of particles into the bloodstream of humans or rats with subsequent excretion through the feces. In addition, standardized guideline-mandated subchronic oral toxicity studies in rats demonstrate very low toxicity effects with NOAELs of >1000 mg/kg bw/day. Additional issues which are summarized in detail in this review are: 1) Methodologies for implementing the Nano Risk Framework - a process for ensuring the responsible development of products containing nanoscale materials; and 2) Safe-handling of nanomaterials in the laboratory.

A comparison of three methods for integrating historical information for Bayesian model averaged benchmark dose estimation.

The benchmark dose (BMD) approach has been accepted as a valuable tool for risk assessment but still faces significant challenges associated with combining environmental hazard information from multiple sources and selecting an appropriate BMD/BMDL estimate from the results of a set of acceptable dose-response models. The main objective of this study is to compare and examine how historical information, especially incompatible data, can impact the Bayesian model averaged BMD estimate through different integration methods. Based on the Bayesian model averaging (BMA) for the benchmark dose estimation, three methods of integration are investigated: (1) pooled data analysis, which combines all dose groups into one dataset; (2) the Bayesian hierarchical model, which takes both between-study and within-study uncertainty into account by building multiple levels of distributions to quantitatively describe parameters in dose-response models; and (3) the power prior method, which allows researchers to weigh the prior information incorporated through a power parameter. Combined historical information can have different levels of impact on the current model weight and BMD estimates depending on the method of integration. The pooled data analysis, which has the largest impact on the current BMA BMD estimate, has limited applicability and might be statistically and biologically flawed. The Bayesian hierarchical model, with a reasonable structure to combine information, can slightly change the current estimates of the model weights and BMD. The power prior method has little influence on current estimates when data are highly incompatible even if the prior information is fully considered.

Assessment of RTG-W1, RTL-W1, and PLHC-1 fish cell lines for genotoxicity testing of environmental pollutants by means of a Fpg-modified comet assay.

In a context of growing awareness of aquatic pollution impacts, there is an increasing need to develop methods for hazard and risk assessment of pollutants. For this purpose, in vitro models such as fish cell lines warrant to be evaluated as possible alternative to in vivo fish testing, and new toxicity endpoints such as genotoxicity deserve to be considered. This study assesses the interest of the formamido pyrimidine glycosylase (Fpg)-modified comet assay applied to three fish cell lines (RTL-W1, RTG-W1, and PLHC-1) regarding the sensitivity of the system for measuring genotoxicity of various classes of pollutants. Cytochrome P450-dependent EROD activity has also been measured to evaluate the importance of the biotransformation capacity of the cell lines in genotoxicity assessment. For all cell lines and chemicals tested, a concentration dependent genotoxic effect was observed with a 10- to 1000-fold increased sensitivity when using the Fpg-protocol compared to the standard comet assay. Such a modified assay led in particular to improve the detection threshold of oxidative and alkylating DNA damages following exposure at environmentally relevant contaminant concentrations and could partly compensate for the lower sensitivity of cell lines versus whole organism testing often cited as a limit of in vitro testing.

Comparison of PCDD/F and dl-PCB levels in Turkish foodstuffs: industrial versus rural, local versus supermarket products, and assessment of dietary intake.

Polychlorinated dibenzo-p-dioxin and dibenzofurans (PCDD/Fs) and dioxin-like and non-dioxin-like (indicator) polychlorinated biphenyls (PCBs) were monitored in various foodstuffs of animal origin and edible oil samples obtained from two different cities in Turkey both rural and industrial. Total dioxin+dioxin-like PCBs and indicator PCB concentrations of pooled samples ranged 0.20-4.19 pg World Health Organization-Toxic Equivalency (WHO-TEQ)(1998)/g fat and 57.2-1710 pg/g fat, respectively. The dominant congeners were 2,3,4,7,8-PeCDF, 1,2,3,7,8-PeCDD, 2,3,7,8-TCDD and PCB126. Dietary intake of dioxin+dioxin-like PCBs and indicator PCBs from fish, dairy products, edible oil, egg and meat was 0.509 pg WHO-TEQ1998/kg bw (body weight)/day and 839 pg/kg bw/day in Afyon and 0.588 pg WHO-TEQ1998/ kg bw/day and 1070 pg/kg bw/day in Kocaeli, respectively. The major contributors to total exposure were dairy products and fish. Despite the unexplained high contamination level in an individual egg sample from Kocaeli, average concentration levels in Turkey, even in industrialized regions, were low compared to reported concentrations in Western Europe. Exposure levels were well below the tolerable daily intake (TDI) of 2 pg WHO-TEQ1998/kg body weight.

Assessment of seasonality in exposure to dioxins, furans and dioxin-like PCBs by using long-term food-consumption data.

According to the European Food Safety Authority (EFSA) guidance related to uncertainties in dietary exposure assessment, exposure assessment based on short-term food-consumption surveys, such as 24-h recalls or 2-day records, tend to overestimate long-term exposure because of the assumption that the dietary pattern will be similar day after day over a lifetime. The aim of this study was to make an assessment of dietary exposure to polychlorinated dibenzodioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs), also called 'dioxins' and 'dioxin-like PCBs', using long-term household purchase and consumption survey data collected by TNS-Secodip. Weekly purchases of the major dioxins and dl-PCB vector products of these contaminants were collected for 328 single-person households, who participated at TNS-Secodip consumption surveys from 2003 to 2005 and who were single-person households in order to estimate better their consumption. These data were combined with average contamination levels of food products. Weekly gross average exposure was estimated at 10.2 pg toxic equivalent (WHO TEQ) kg(-1) bw week(-1) (95% confidence interval [9.6, 10.9]). According to the typical shape of the distribution of individual weekly exposures, it is sensible to fit an exponential law to these data. The mean was therefore 12.1 pg WHO TEQ kg(-1) bw week(-1). This value is higher than the arithmetic mean because it better takes into account inter-individual variability. It was estimated that about 20% of persons in this sample were exceeding the current health-based guidance value mainly due to high consumption of seafood and/or dairy products. Thanks to long survey duration (3 years) and the weekly recording of food consumption, it was possible to demonstrate the actual seasonality of dietary exposure to dioxins and dl-PCBs with a maximum between March and September; similar seasonality is observable for fish consumption. Autoregressive integrated moving average (ARIMA) models were adjusted to the time series and it was demonstrated that the number of times the upper limit of confidence intervals exceeds the provisional tolerable weekly intake (PTWI) is about 15 weeks per year on average. Finally, compared with the results obtained from data collected in the short-term surveys (1 week), this study does not suggest that short-term consumption surveys tend to overestimate the long-term exposure.

Polybrominated diphenyl ethers in food and associated human daily intake assessment considering bioaccessibility measured by simulated gastrointestinal digestion.

The concentrations of PBDEs in 299 vegetable and animal-based food samples of 31 species, collected in Shanghai, China, and the bioaccessibility of PBDEs in part of the samples were determined. The PBDE concentrations ranged from 0 to 1245.4pgg(-1) with animal-based food containing more PBDEs than vegetables. The bioaccessibility of PBDEs, determined by a method simulating human gastrointestinal digestion process, were from 2.6% to 39.9% in vegetables, and from 5.2% to 105.3% in animal-based food. For animal-based food, good correlations were observed between the bioaccessibility of PBDEs and the fat content, thus the fat content in animal-based food was able to be used to estimate the bioaccessibility of PBDEs. The total daily intake of PBDEs via ingestion of vegetables and animal-based food for an average Shanghai resident was estimated as 13235.7 and 13668.0pg d(-1), respectively, but the amounts available for human absorption were reduced to 2674.4 and 4316.6pgd(-1) after the PBDE bioaccessibility was considered. Finally, the contributions of different food groups to the total daily intake of PBDEs were evaluated. The results revealed that, when not considering the bioaccessibility of PBDEs, vegetables were the leading contributor (49.2%), followed by fish (34.0%). However, the sequence was reversed after the PBDE bioaccessibility was taken into account. The results indicated that human exposure to PBDEs via food ingestion might have been significantly overestimated and the exposure assessment could be misleading if the bioaccessibility of PBDEs was not considered.

Assessment of bisphenol A exposure in Korean pregnant women by physiologically based pharmacokinetic modeling.

The objective of this study was to predict the exposure to bisphenol A (BPA) after oral intake in human blood and tissues using physiologically based pharmacokinetic (PBPK) modeling. A refined PBPK model was developed taking into account of glucuronidation, biliary excretion, and slow absorption of BPA in order to describe the second peak of BPA observed following oral intake. This developed model adequately described the second peak and BPA concentrations in blood and various tissues in rats after oral administration. A prospective validation study in rats additionally supported the proposed model. For extrapolation to humans, a daily oral BPA dose of 0.237 mg/70 kg/d or 0.0034 mg/kg/d was predicted to achieve an average steady-state blood concentration of 0.0055 ng/ml (median blood BPA concentration in Korean pregnant women). This dose was lower than the reference dose (RfD, 0.016 mg/kg/d) and the tolerable daily intake established by the European Commission (10 µg/kg/d). Data indicate that enterohepatic recirculation may be toxicologically important as this pathway may increase exposure and terminal half-life of BPA in humans.

The significance of the Druckrey-Küpfmüller equation for risk assessment--the toxicity of neonicotinoid insecticides to arthropods is reinforced by exposure time.

The essence of the Druckrey-Küpfmüller equation dtn = constant (where d = daily dose and t = exposure time-to-effect, with n > 1) for chemical carcinogens is that the total dose required to produce the same effect decreases with decreasing exposure levels, even though the exposure times required to produce the same effect increase with decreasing exposure levels. Druckrey and Küpfmüller inferred that if both receptor binding and the effect are irreversible, exposure time would reinforce the effect. The Druckrey-Küpfmüller equation explains why toxicity may occur after prolonged exposure to very low toxicant levels. Recently, similar dose-response characteristics have been established for the toxicity of the neonicotinoid insecticides imidacloprid and thiacloprid to arthropods. This observation is highly relevant for environmental risk assessment. Traditional approaches that consider toxic effects at fixed exposure times are unable to allow extrapolation from measured endpoints to effects that may occur at other times of exposure. Time-to-effect approaches that provide information on the doses and exposure times needed to produce toxic effects on tested organisms are required for prediction of toxic effects for any combination of concentration and time in the environment.

Considering changes in exposure and sensitivity in an early life cumulative risk assessment.

A cumulative risk assessment is generally intended to address concurrent exposure by all exposure routes to a group of chemicals that share a common mechanism of toxicity. However, the contribution of different exposure routes will change over time. This is most critical when estimating risks to infants and children because their exposure sources change rapidly during the first few years of life because of dietary and behavioral changes. In addition, there may be changes in sensitivity to toxicants during this time period, associated with various developmental stages. Traditional risk assessments do not address this progression. Examples of how these factors might be incorporated into an early life risk assessment are provided for lead, dioxins and furans, and organophosphate pesticides. The same concepts may apply to other potentially susceptible subpopulations, such as the elderly.

Reconstructing population exposures to environmental chemicals from biomarkers: challenges and opportunities.

A conceptual/computational framework for exposure reconstruction from biomarker data combined with auxiliary exposure-related data is presented, evaluated with example applications, and examined in the context of future needs and opportunities. This framework employs physiologically based toxicokinetic (PBTK) modeling in conjunction with numerical "inversion" techniques. To quantify the value of different types of exposure data "accompanying" biomarker data, a study was conducted focusing on reconstructing exposures to chlorpyrifos, from measurements of its metabolite levels in urine. The study employed biomarker data as well as supporting exposure-related information from the National Human Exposure Assessment Survey (NHEXAS), Maryland, while the MENTOR-3P system (Modeling ENvironment for TOtal Risk with Physiologically based Pharmacokinetic modeling for Populations) was used for PBTK modeling. Recently proposed, simple numerical reconstruction methods were applied in this study, in conjunction with PBTK models. Two types of reconstructions were studied using (a) just the available biomarker and supporting exposure data and (b) synthetic data developed via augmenting available observations. Reconstruction using only available data resulted in a wide range of variation in estimated exposures. Reconstruction using synthetic data facilitated evaluation of numerical inversion methods and characterization of the value of additional information, such as study-specific data that can be collected in conjunction with the biomarker data. Although the NHEXAS data set provides a significant amount of supporting exposure-related information, especially when compared to national studies such as the National Health and Nutrition Examination Survey (NHANES), this information is still not adequate for detailed reconstruction of exposures under several conditions, as demonstrated here. The analysis presented here provides a starting point for introducing improved designs for future biomonitoring studies, from the perspective of exposure reconstruction; identifies specific limitations in existing exposure reconstruction methods that can be applied to population biomarker data; and suggests potential approaches for addressing exposure reconstruction from such data.

Separation of uncertainty and interindividual variability in human exposure modeling.

The NORMTOX model predicts the lifetime-averaged exposure to contaminants through multiple environmental media, that is, food, air, soil, drinking and surface water. The model was developed to test the coherence of Dutch environmental quality objectives (EQOs). A set of EQOs is called coherent if simultaneous exposure to different environmental media that are all polluted up to their respective EQOs does not result in exceeding the acceptable or tolerable daily intake (ADI or TDI). Aim of the present study is to separate the impact of uncertainty and interindividual variability in coherence predictions with the NORMTOX model. The method is illustrated in a case study for chlorfenvinphos, mercury and nitrate. First, ANOVA was used to calculate interindividual variability in input parameters. Second, nested Monte Carlo simulation was used to propagate uncertainty and interindividual variability separately. Lifetime-averaged exposure to chlorfenvinphos, mercury and nitrate was modeled for the Dutch population. Output distributions specified the population fraction at risk, due to a particular exposure, and the reliability of this risk. From the case study, it was obtained that at lifelong exposure to all media polluted up to their standard, 100% of the Dutch population exceeds the ADI for chlorfenvinphos, 15% for mercury and 0% for nitrate. Variance in exposure to chlorfenvinphos, mercury and nitrate is mostly caused by interindividual variability instead of true uncertainty. It is concluded that the likelihood that ADIs of chlorfenvinphos and mercury will be exceeded should be further explored. If exceeding is likely, decision makers should focus on identification of high-risk subpopulations, rather than on additional research to obtain more accurate estimates for particular parameters.

Approaches for applications of physiologically based pharmacokinetic models in risk assessment.

Physiologically based pharmacokinetic (PBPK) models are particularly useful for simulating exposures to environmental toxicants for which, unlike pharmaceuticals, there is often little or no human data available to estimate the internal dose of a putative toxic moiety in a target tissue or an appropriate surrogate. This article reviews the current state of knowledge and approaches for application of PBPK models in the process of deriving reference dose, reference concentration, and cancer risk estimates. Examples drawn from previous U.S. Environmental Protection Agency (EPA) risk assessments and human health risk assessments in peer-reviewed literature illustrate the ways and means of using PBPK models to quantify the pharmacokinetic component of the interspecies and intraspecies uncertainty factors as well as to conduct route to route, high dose to low dose and duration extrapolations. The choice of the appropriate dose metric is key to the use of the PBPK models for the various applications in risk assessment. Issues related to whether uncertainty factors are most appropriately applied before or after derivation of human equivalent dose (or concentration) continue to be explored. Scientific progress in the understanding of life stage and genetic differences in dosimetry and their impacts on variability in susceptibility, as well as ongoing development of analytical methods to characterize uncertainty in PBPK models, will make their use in risk assessment increasingly likely. As such, it is anticipated that when PBPK models are used to express adverse tissue responses in terms of the internal target tissue dose of the toxic moiety rather than the external concentration, the scientific basis of, and confidence in, risk assessments will be enhanced.

Neurodevelopmental toxicity of methylmercury: Laboratory animal data and their contribution to human risk assessment.

Methylmercury (MeHg) is one of the most significant public health hazards. The clinical findings in the victims of the Japanese and Iraqi outbreaks have disclosed the pronounced susceptibility of the developing brain to MeHg poisoning. This notion has triggered worldwide scientific attention toward the long-term consequences of prenatal exposure on child development in communities with chronic low level dietary exposure. MeHg neurodevelopmental effects have been extensively investigated in laboratory animals under well-controlled exposure conditions. This article provides an updated overview of the main neuromorphological and neurobehavioral changes reported in non-human primates and rodents following developmental exposure to MeHg. Different aspects of MeHg's effects on the immature organism are reported, with particular reference to the delayed onset of symptoms and the persistency of central nervous system (CNS) injury/dysfunction. Particular attention is paid to the comparative toxicity assessment across species, and to the degree of concordance/discordance between human and animal data. The contribution of animal studies to define the role of potential effect modifiers and variables on MeHg dose-response relationships is also addressed. The ultimate goal is to discuss the relevance of laboratory animal results, as a complementary tool to human data, with regard to the human risk assessment process.

Simulated impact of a fish based shift in the population n--3 fatty acids intake on exposure to dioxins and dioxin-like compounds.

Due to the favourable health effects of LC n-3 PUFAs, marine products have been recognised as a food group of special importance in the human diet. However, seafood is susceptible to contamination by lipophilic organic pollutants. The objective of this study was to evaluate intake levels of PCDDs, PCDFs and dioxin-like PCBs, by a probabilistic Monte Carlo procedure, in relation to the recommendation on LC n-3 PUFAs given by Belgian Federal Health Council. Regarding the recommendation, two scenarios were developed differing in LC n-3 PUFAs intake: a 0.3 E% and a 0.46 E% scenario. Total exposure to dioxins and dioxin-like substances in the 0.3 E% LC n-3 PUFAs scenario ranges from 2.31 pg TEQ/kg bw/day at the 5th percentile, over 4.37 pg TEQ/kgbw/day at the 50th percentile to 8.41 pg TEQ/kgbw/day at the 95th percentile. In the 0.46 E% LC n-3 PUFAs scenario, 5, 50 and 95th percentile are exposed to 2.74, 5.52 and 9.98 pg TEQ/kgbw/day, respectively. Therefore, if the recommended LC n-3 PUFAs intake would be based on fish consumption as the only extra source, the majority of the study population would exceed the proposed health based guidance values for dioxins and dioxin-like substances.

Physiologically-based pharmacokinetic modeling of benzene in humans: a Bayesian approach.

Benzene is myelotoxic and leukemogenic in humans exposed at high doses (>1 ppm, more definitely above 10 ppm) for extended periods. However, leukemia risks at lower exposures are uncertain. Benzene occurs widely in the work environment and also indoor air, but mostly below 1 ppm, so assessing the leukemia risks at these low concentrations is important. Here, we describe a human physiologically-based pharmacokinetic (PBPK) model that quantifies tissue doses of benzene and its key metabolites, benzene oxide, phenol, and hydroquinone after inhalation and oral exposures. The model was integrated into a statistical framework that acknowledges sources of variation due to inherent intra- and interindividual variation, measurement error, and other data collection issues. A primary contribution of this work is the estimation of population distributions of key PBPK model parameters. We hypothesized that observed interindividual variability in the dosimetry of benzene and its metabolites resulted primarily from known or estimated variability in key metabolic parameters and that a statistical PBPK model that explicitly included variability in only those metabolic parameters would sufficiently describe the observed variability. We then identified parameter distributions for the PBPK model to characterize observed variability through the use of Markov chain Monte Carlo analysis applied to two data sets. The identified parameter distributions described most of the observed variability, but variability in physiological parameters such as organ weights may also be helpful to faithfully predict the observed human-population variability in benzene dosimetry.

TCDD exposure-response analysis and risk assessment.

We examined the relation between cancer mortality and time-dependent cumulative exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) estimated from a concentration- and age-dependent kinetic model of elimination, and we estimated incremental cancer risks at age 75. Data from the National Institute for Occupational Safety and Health study of 3,538 workers with occupational exposure to TCDD were analyzed using standardized mortality ratios and Cox regression procedures. Analyses adjusted for potential confounding by age, year of birth, and race and considered exposure lag periods of 0, 10, or 15 years. Other potential confounders including smoking and other occupational exposures were evaluated indirectly. To explore the influence of extreme values of cumulative TCDD ppt-years, we restricted the analysis to observations with exposure below the 95th percentile or used logarithmic (ln) transformed exposure values. We applied penalized smoothing splines to examine variation in the exposure-response relation across the exposure range. TCDD was not statistically significantly associated with cancer mortality using the full data set, regardless of the lag period. When we restricted the analysis to observations with exposure below the 95th percentile, TCDD was associated positively with cancer mortality, particularly when a 15-year lag was applied (untransformed exposure data: regression coefficient , standard error (s.e.) = 1.4 x 10(-6), p < 0.05; ln-transformed exposure data: , s.e. = 2.9 x 10(-2), p < 0.05). The estimated incremental lifetime risk of mortality at age 75 from all cancers was about 6 to more than 10 times lower than previous estimates derived from this cohort using exposure models that did not consider the age and concentration dependence of TCDD elimination.