Background: Cadmium is a widespread environmental pollutant that has been shown to exert toxic effects on kidney and bones in humans after long-term exposure. Urinary cadmium concentration is considered a good biomarker of accumulated cadmium in kidney, and diet is the main source of cadmium among nonsmokers. Objective: Modeling the link between urinary cadmium and dietary cadmium intake is a key step in the risk assessment of long-term cadmium exposure. There is, however, little knowledge on how this link may vary, especially for susceptible population strata. Methods: We used a large population-based study (the Swedish Mammography Cohort), with repeated dietary intake data covering a period of 20 years, to compare estimated dietary cadmium intake with urinary cadmium concentrations on an individual basis. A modified version of the Nordberg-Kjellström model and a one-compartment model were evaluated in terms of their predictions of urinary cadmium. We integrated the models and quantified the between-person variability of cadmium half-life in the population. Finally, sensitivity analyses and Monte Carlo simulations were performed to illustrate how the latter model could serve as a robust tool supporting the risk assessment of cadmium in humans. Results: The one-compartment population model appeared to be an adequate modeling option to link cadmium intake to urinary cadmium and to describe the population variability. We estimated the cadmium half-life to be about 11.6 years, with about 25% population variability. Conclusions: Population toxicokinetic models can be robust and useful tools for risk assessment of chemicals, because they allow quantification and integration of population variability in toxicokinetics.

Physiologically based pharmacokinetic (PBPK) models are used in mode-of-action based risk and safety assessments to estimate internal dosimetry in animals and humans. When used in risk assessment, these models can provide a basis for extrapolating between species, doses, and exposure routes or for justifying nondefault values for uncertainty factors. Characterization of uncertainty and variability is increasingly recognized as important for risk assessment; this represents a continuing challenge for both PBPK modelers and users. Current practices show significant progress in specifying deterministic biological models and nondeterministic (often statistical) models, estimating parameters using diverse data sets from multiple sources, using them to make predictions, and characterizing uncertainty and variability of model parameters and predictions. The International Workshop on Uncertainty and Variability in PBPK Models, held 31 Oct–2 Nov 2006, identified the state-of-the-science, needed changes in practice and implementation, and research priorities. For the short term, these include (1) multidisciplinary teams to integrate deterministic and nondeterministic/statistical models; (2) broader use of sensitivity analyses, including for structural and global (rather than local) parameter changes; and (3) enhanced transparency and reproducibility through improved documentation of model structure(s), parameter values, sensitivity and other analyses, and supporting, discrepant, or excluded data. Longer-term needs include (1) theoretical and practical methodological improvements for nondeterministic/statistical modeling; (2) better methods for evaluating alternative model structures; (3) peer-reviewed databases of parameters and covariates, and their distributions; (4) expanded coverage of PBPK models across chemicals with different properties; and (5) training and reference materials, such as cases studies, bibliographies/glossaries, model repositories, and enhanced software. The multidisciplinary dialogue initiated by this Workshop will foster the collaboration, research, data collection, and training necessary to make characterizing uncertainty and variability a standard practice in PBPK modeling and risk assessment.

Heated tobacco products (HTPs) are novel products that allow users to inhale nicotine by heating (350 °C) reconstituted tobacco rather than combustion (900 °C) as in conventional cigarettes. HTP sticks containing reconstituted tobacco come in various flavours such as menthol, citrus, etc., like electronic cigarette liquids. Thus, the composition of HTP aerosol will also vary according to the flavouring agents added. Overall, the content of toxic chemicals in HTP aerosol appears to be lower than in cigarette smoke. However, the concentrations of more than twenty harmful and potentially harmful constituents have been reported to be higher in HTP aerosol than in cigarette smoke. Further, several toxic compounds not detected in cigarette smoke are also reported in HTP aerosol. Thus, the risks of HTP use remain unknown. Most of the available data on the composition and health effects of mainstream HTP aerosol exposure are generated by the tobacco industry. Few independent studies have reported short-term pathophysiological effects of HTP use. Currently available HTP toxicity data are mainly on the pulmonary and cardiovascular systems. Moreover, there are no long-term toxicity data and, therefore, the claims of the tobacco industry regarding HTPs as a safer alternative to traditional combustible cigarettes are unsubstantiated. Furthermore, HTP aerosol contains the highly addictive substance nicotine, which is harmful to the adolescent brain, developing foetuses, pregnant women, and also adults. Hence, comprehensive studies addressing the safety profiling related to long-term HTP use are warranted. With this background, the following review summarizes the current state of knowledge on HTP toxicity on four broad lines: composition of mainstream HTP aerosol compared to traditional combustible cigarette smoke, biomarkers of HTP exposure, health effects of HTP exposure, and the harm reduction aspect.

Occupational exposure limits (OELs) serve as health-based benchmarks against which measured or estimated workplace exposures can be compared. In the years since the introduction of OELs to public health practice, both developed and developing countries have established processes for deriving, setting, and using OELs to protect workers exposed to hazardous chemicals. These processes vary widely, however, and have thus resulted in a confusing international landscape for identifying and applying such limits in workplaces. The occupational hygienist will encounter significant overlap in coverage among organizations for many chemicals, while other important chemicals have OELs developed by few, if any, organizations. Where multiple organizations have published an OEL, the derived value often varies considerably-reflecting differences in both risk policy and risk assessment methodology as well as access to available pertinent data. This article explores the underlying reasons for variability in OELs, and recommends the harmonization of risk-based methods used by OEL-deriving organizations. A framework is also proposed for the identification and systematic evaluation of OEL resources, which occupational hygienists can use to support risk characterization and risk management decisions in situations where multiple potentially relevant OELs exist.

To assess the potential toxicity of nanoparticles (NPs), information concerning their uptake and disposition (biokinetics) is essential. Experience with industrial chemicals and pharmaceutical drugs reveals that biokinetics can be described and predicted accurately by physiologically-based pharmacokinetic (PBPK) modeling. The nano PBPK models developed to date all concern a single type of NP. Our aim here was to extend a recent model for pegylated polyacrylamide NP in order to develop a more general PBPK model for nondegradable NPs injected intravenously into rats. The same model and physiological parameters were applied to pegylated polyacrylamide, uncoated polyacrylamide, gold, and titanium dioxide NPs, whereas NP-specific parameters were chosen on the basis of the best fit to the experimental time-courses of NP accumulation in various tissues. Our model describes the biokinetic behavior of all four types of NPs adequately, despite extensive differences in this behavior as well as in their physicochemical properties. In addition, this simulation demonstrated that the dose exerts a profound impact on the biokinetics, since saturation of the phagocytic cells at higher doses becomes a major limiting step. The fitted model parameters that were most dependent on NP type included the blood:tissue coefficients of permeability and the rate constant for phagocytic uptake. Since only four types of NPs with several differences in characteristics (dose, size, charge, shape, and surface properties) were used, the relationship between these characteristics and the NP-dependent model parameters could not be elucidated and more experimental data are required in this context. In this connection, intravenous biodistribution studies with associated PBPK analyses would provide the most insight.

Seven male volunteers were exposed to 2-butoxyethanol at the Swedish occupational exposure limit (20 ppm or 0.85 mmol/m3) during light physical exercise (50 W) on a bicycle ergometer. The exposure took place in an exposure chamber and lasted 2 h. Expired air was collected at regular time intervals for estimation of the respiratory uptake of the solvent. Arterialized capillary blood and urine were sampled during and after the exposure period and analyzed for 2-butoxyethanol and its metabolite butoxyacetic acid. A new sensitive method for analyzing 2-butoxyethanol in biological specimens is described. 2-Butoxyethanol was derivatized with pentafluorobenzoyl chloride and analyzed by gas chromatography with electron capture detection. The respiratory uptake of 2-butoxyethanol averaged 10.1 mumol/min or 57% of the inspired amount. The concentration in blood reached a plateau level of 7.4 mumol/l. The apparent values of elimination half-time, mean residence time, total blood clearance, and steady-state volume of distribution were 40 min, 42 min, 1.2 1/min and 54 l, respectively. The amount of 2-butoxyethanol excreted in urine was less than 0.03% of the total uptake, while that of butoxyacetic acid ranged from 17 to 55%.