Derivation and application of indoor air screening values for inhalation exposure to semi-volatile organic compounds.

Semi-volatile organic compounds (SVOCs) are being increasingly studied in indoor air. The absence of health-based inhalation exposure guidelines for most SVOCs impedes the interpretation of indoor air concentrations from a health risk context. To accelerate the derivation of screening values for a large number of SVOCs, a tiered framework was developed to evaluate and adjust published hazard assessments for SVOCs to calculate benchmarks relevant for evaluation of inhalation risk. Inhalation screening values were derived for 43 SVOCs considered in this study, most of which required extrapolation from oral exposure guidelines. The screening values were compared to published SVOC concentrations in homes in Canada to evaluate the potential health risks of chronic exposure to SVOCs in indoor residential environments. SVOCs that could be prioritized for further evaluation were dibutyl phthalates (DBP), di(2-ethylhexyl) phthalate (DEHP) and polybrominated diphenyl ethers (PBDEs). The framework could be applied more broadly in the future to derive screening values for other non-traditional indoor air contaminants with limited inhalation hazard data or assessments.

Will worker DNELs derived under the European REACH regulation extend the landscape of occupational exposure guidance values?

Derived no-effect levels for workers (wDNELs) under the European REACH legislation have many aspects in common with occupational exposure limits (OELs). In an attempt to examine under which circumstances wDNELs might be used as exposure guidance outside their intended application, we compared derivation methods, coverage of substances and numerical values of wDNELs against two regulatory OEL lists (European Commission and Sweden) and three sets of recommendations (European SCOEL, German MAK and US ACGIH). Finally, we looked closer at wDNELs where SCOEL concluded that data were insufficient to derive an OEL. Major differences between wDNELs and OELs include regulatory background, intended use, actors involved, substance selection criteria, transparency and procedure of derivation, and operationalisation in terms of risk management measures. As of summer 2018, approximately five times more substances were covered by wDNELs than by the five sets of OELs examined herein. Meanwhile, many occupationally relevant pollutants were not covered by wDNELs, e.g. one-third of Swedish OELs lack corresponding wDNELs. We also note that wDNELs and OELs for the same substance may vary considerably, up to several orders of magnitude. In conclusion, with extensive substance coverage, wDNELs extend the landscape beyond the OELs. That said, important limitations are (1) that many air pollutants relevant for workers' health are not covered by REACH, and (2) concerns for inconsistencies in the derivation of wDNELs and in their level of protection. In particular, that route-to-route extrapolation is a common practice that may be grossly misleading when the effect of concern is local, e.g. sensitisation.

Route-to-route extrapolation of 1,2-dichloroethane studies from the oral route to inhalation using physiologically based pharmacokinetic models.

To help develop a comprehensive, quantitative understanding of the hazards of 1,2-dichloroethane (ethylene dichloride, EDC, CAS No. 107-06-2) exposure by the inhalation route, the results of existing subchronic studies and an extended one-generation reproductive toxicity (EOGRT) study recently conducted by the oral route in rats were extrapolated using a physiologically based pharmacokinetic (PBPK) model. The no observed adverse effects levels (NOAELs) for the endpoints of neurotoxicity and reproductive/developmental toxicity were the highest tested doses of 169 and 155 mg/kg-day, respectively. These NOAELs were equivalent to continuous exposure of rats to minimums of 76 ppm and 62 ppm EDC, respectively, using total metabolism of EDC as the dose metric that is equivalent in the oral and inhalation scenarios. In contrast, the subchronic study NOAEL of 37.5 mg/kg-day corresponded to continuous inhalation of 4.4 ppm EDC, based on equivalent extrahepatic metabolism. The selection of the internal metric which serves to establish route-to-route equivalency was found to profoundly influence the NOAEL-equivalent inhalation exposure concentration and thus will be a key determinant of inhalation toxicity reference criteria developed on the basis of EDC studies conducted by the oral route.

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.

Recommendations for the reference concentration of cadmium exposure based on a physiologically based toxicokinetic model integrated with a human respiratory tract model.

Cadmium (Cd) poses a significant threat to human health. However, chronic toxicity parameters for inhalation exposure are lacking, especially for noncritical systemic toxic effects. A physiologically based toxicokinetic (PBTK) model can be used to extrapolate toxicity parameters across various exposure routes. We combined a PBTK model with a human respiratory tract (HRT) model, which is applicable to the general population and capable of simulating the deposition and clearance processes of various airborne Cd compounds in the respiratory tract. Monte Carlo analysis was used to simulate the distribution of sensitive parameters to reflect individual variability. Validation based on datasets from general and occupational populations showed that the improved model had acceptable or better predictive performance, outperforming the original model with a 14.45 % decrease in the root mean square error (RMSE). Using this PBTK-HRT model, we extrapolated toxicity parameters from oral exposure to inhalation exposure for four systemic toxic effects with doseresponse relationships but no known inhalation toxicity parameters, and ultimately recommended reference concentrations (RfCs) for four diseases (chronic kidney disease: 0.01 µg/m3, osteoporosis: 0.01 µg/m3, stroke: 0.04 µg/m3, diabetes mellitus: 0.13 µg/m3), contributing to a comprehensive assessment of the health risks of Cd inhalation exposure. ENVIRONMENTAL IMPLICATION: Cadmium (Cd), a heavy metal, can cause lung cancer, chronic kidney disease, and osteoporosis and pose a significant threat to human health. We combined a physiologically based toxicokinetic (PBTK) model with a human respiratory tract (HRT) model to achieve better predictive performance and wider applicability; this model was subsequently employed for route-to-route extrapolation of toxicity parameters. Additionally, for the first time, we focused on multiple subchronic and chronic systemic toxic effects in addition to critical effects and derived their reference concentrations (RfCs), which can be used to assess the health risk of Cd inhalation exposure more comprehensively and accurately.

Occupational exposure limits for reproductive toxicants - A comparative analysis.

We investigated the level of protection of reproductive and developmental toxicity offered through occupational exposure limits (OELs) and Derived No-Effect Levels for workers' inhalation exposure (wDNELs). We compared coverage of substances that have a harmonised classification as reproductive toxicant 1 A or 1B (Repr.1 A/B), numerical values and scientific basis of 12 lists of OELs and wDNELs from REACH Registrants' and the Committee for Risk Assessment. Across the 14 sources of OELs and wDNELs, 53 % of the Repr1A/B-substances had at least one exposure limit (counting groups of metals as one entry). Registrants' wDNELs covered the largest share, 40 %. The numerical values could be highly variable for the same substance across the lists. How often reproductive toxicity is identified as the critical effect varies between the examined lists, both due to different assessments of the same substance and different substance coverage. Reviewing the margin of safety to reproductive toxicity cited in the documents, we found that 15 % of safety margins were lower to reproductive toxicity than the critical effect. To conclude, neither the REACH nor work environment legislation supply wDNELs or OELs for a substantial share of known reproductive toxicants. EU OELs cover among the fewest substances in the range, and in many cases national OELs or wDNELs are set at more conservative levels.

Physiologically-based pharmacokinetic model for Fentanyl in support of the development of Provisional Advisory Levels.

Provisional Advisory Levels (PALs) are tiered exposure limits for toxic chemicals in air and drinking water that are developed to assist in emergency responses. Physiologically-based pharmacokinetic (PBPK) modeling can support this process by enabling extrapolations across doses, and exposure routes, thereby addressing gaps in the available toxicity data. Here, we describe the development of a PBPK model for Fentanyl - a synthetic opioid used clinically for pain management - to support the establishment of PALs. Starting from an existing model for intravenous Fentanyl, we first optimized distribution and clearance parameters using several additional IV datasets. We then calibrated the model using pharmacokinetic data for various formulations, and determined the absorbed fraction, F, and time taken for the absorbed amount to reach 90% of its final value, t90. For aerosolized pulmonary Fentanyl, F=1 and t90<1 min indicating complete and rapid absorption. The F value ranged from 0.35 to 0.74 for oral and various transmucosal routes. Oral Fentanyl was absorbed the slowest (t90~300 min); the absorption of intranasal Fentanyl was relatively rapid (t90~20-40 min); and the various oral transmucosal routes had intermediate absorption rates (t90~160-300 min). Based on these results, for inhalation exposures, we assumed that all of the Fentanyl inhaled from the air during each breath directly, and instantaneously enters the arterial circulation. We present model predictions of Fentanyl blood concentrations in oral and inhalation scenarios relevant for PAL development, and provide an analytical expression that can be used to extrapolate between oral and inhalation routes for the derivation of PALs.

Relative source allocation of TDI to drinking water for derivation of a criterion for chloroform: a Monte-Carlo and multi-exposure assessment.

Drinking water quality standard (DWQS) criteria for chemicals for which there is a threshold for toxicity are derived by allocating a fraction of tolerable daily intake (TDI) to exposure from drinking water. We conducted physiologically based pharmacokinetic model simulations for chloroform and have proposed an equation for total oral-equivalent potential intake via three routes (oral ingestion, inhalation, and dermal exposures), the biologically effective doses of which were converted to oral-equivalent potential intakes. The probability distributions of total oral-equivalent potential intake in Japanese people were estimated by Monte Carlo simulations. Even when the chloroform concentration in drinking water equaled the current DWQS criterion, there was sufficient margin between the intake and the TDI: the probability that the intake exceeded TDI was below 0.1%. If a criterion that the 95th percentile estimate equals the TDI is regarded as both providing protection to highly exposed persons and leaving a reasonable margin of exposure relative to the TDI, then the chloroform drinking water criterion could be a concentration of 0.11mg/L. This implies a daily intake equal to 34% of the TDI allocated to the oral intake (2L/d) of drinking water for typical adults. For the highly exposed persons, inhalation exposure via evaporation from water contributed 53% of the total intake, whereas dermal absorption contributed only 3%.

Proper knowledge on toxicokinetics improves human hazard testing and subsequent health risk characterisation. A case study approach.

In the current EU legislative frameworks on chemicals safety, the requirements with respect to information on general kinetic parameters (absorption, distribution, metabolism and excretion or ADME) or integrated toxicokinetic parameters (TK, i.e. plasma concentration-time curve, area under the curve etcetera) in humans and experimental animals vary widely. For agrochemicals and cosmetics, there are regulatory requirements whereas for other frameworks, such as food ingredients, biocides, consumer products and high production volume chemicals (REACH) there are very little or no requirements. This paper presents case studies that illustrate the importance of ADME and TK data in regulatory risk characterisations. The examples were collected by interviewing regulatory risk assessors from various chemicals (non-pharmaceutical) frameworks. The case studies illustrate how (1) applying ADME/TK in an early phase of toxicity testing can be used to improve study design and support the 3R-goals and how (2) increased use of ADME/TK data can improve the final risk assessment.

Considerations for Applying Route-to-Route Extrapolation to Assess the Safety of Oral Exposure to Substances.

The safety evaluation of oral exposure to substances, such as food ingredients, additives, and their constituents, relies primarily on a careful evaluation and analysis of data from oral toxicity studies. When relevant oral toxicity studies are unavailable or may have significant data gaps that make them inadequate for use in safety evaluations, data from non-oral toxicity studies in animals, such as studies on inhalation, dermal exposure, etc., might be used in support of or in place of oral toxicity studies through route-to-route (R-t-R) extrapolation. R-t-R extrapolation is applied on a case-by-case basis as it requires attention to and comparison of substance-specific toxicokinetic (TK) and toxicodynamic (TD) data for oral and non-oral exposure routes. This article provides a commentary on the utility of R-t-R extrapolation to assess the safety of oral exposure to substances, with an emphasis on the relevance of TK and systemic toxicity data.

The margin of internal exposure (MOIE) concept for dermal risk assessment based on oral toxicity data - A case study with caffeine.

Route-to-route extrapolation is a common part of human risk assessment. Data from oral animal toxicity studies are commonly used to assess the safety of various but specific human dermal exposure scenarios. Using theoretical examples of various user scenarios, it was concluded that delineation of a generally applicable human dermal limit value is not a practicable approach, due to the wide variety of possible human exposure scenarios, including its consequences for internal exposure. This paper uses physiologically based kinetic (PBK) modelling approaches to predict animal as well as human internal exposure dose metrics and for the first time, introduces the concept of Margin of Internal Exposure (MOIE) based on these internal dose metrics. Caffeine was chosen to illustrate this approach. It is a substance that is often found in cosmetics and for which oral repeated dose toxicity data were available. A rat PBK model was constructed in order to convert the oral NOAEL to rat internal exposure dose metrics, i.e. the area under the curve (AUC) and the maximum concentration (Cmax), both in plasma. A human oral PBK model was constructed and calibrated using human volunteer data and adapted to accommodate dermal absorption following human dermal exposure. Use of the MOIE approach based on internal dose metrics predictions provides excellent opportunities to investigate the consequences of variations in human dermal exposure scenarios. It can accommodate within-day variation in plasma concentrations and is scientifically more robust than assuming just an exposure in mg/kg bw/day.

Evaluation of route-to-route extrapolation factors based on assessment of repeated dose toxicity studies compiled in the database RepDose®.

The majority of repeated dose toxicity studies are available for the oral route. For risk assessment, however, data are needed from the relevant exposure route, i.e. inhalation or dermal. Instead of conducting additional animal studies, route-to-route (R2R) extrapolation may be performed. To explore uncertainties associated with this approach, we derived extrapolation factors (EF) based on no/lowest effect levels (NOELs/LOELs) in the Fraunhofer RepDose® database. For R2R extrapolation oral-to-inhalation 246 study pairs on 110 chemicals were analyzed. Systemic effects triggered the LOELs in the underlying inhalation studies in 49.2%, local effects in 21.9% and both local and systemic effects in 30.9% of the data pairs. For systemic effects in inhalation studies an EF of 2.2 (95% confidence interval: 1.2-3.1) was derived, for local effects, the EF was 4.4 (95% confidence interval: 2.0-8.6), and the EF without distinguishing local or systemic effects (any EF) was 3.2 (95%, confidence interval: 1.7-5.0). Calculation with LOELs instead of NOELs, exposure duration and intrinsic properties of the chemical (toxicity or physicochemical properties) did not influence the EF significantly. For R2R extrapolation oral-to-dermal 46 study pairs on 28 chemicals were analyzed. An overall EF of 0.4 (95%, confidence interval: 0.2-0.9) was obtained. Here, we found a significant difference of EFs for low and high toxic chemicals. Overall, we conclude that reliable systemic NOELs/LOELs can be obtained for inhalation studies via R2R extrapolation from oral studies. Based on the data for any EF we propose to use an EF of 3, which covers also the uncertainty that unexpected local effects may occur in an inhalation study. For the dermal route, our dataset was too small to allow general conclusions, but the results so far do suggest that the current ECHA guidance is conservative when assuming that dermal absorption is as high as oral absorption.

Application of physiologically-based toxicokinetic modelling in oral-to-dermal extrapolation of threshold doses of cosmetic ingredients.

The application of physiologically based toxicokinetic (PBTK) modelling in route-to-route (RtR) extrapolation of three cosmetic ingredients: coumarin, hydroquinone and caffeine is shown in this study. In particular, the oral no-observed-adverse-effect-level (NOAEL) doses of these chemicals are extrapolated to their corresponding dermal values by comparing the internal concentrations resulting from oral and dermal exposure scenarios. The PBTK model structure has been constructed to give a good simulation performance of biochemical processes within the human body. The model parameters are calibrated based on oral and dermal experimental data for the Caucasian population available in the literature. Particular attention is given to modelling the absorption stage (skin and gastrointestinal tract) in the form of several sub-compartments. This gives better model prediction results when compared to those of a PBTK model with a simpler structure of the absorption barrier. In addition, the role of quantitative structure-property relationships (QSPRs) in predicting skin penetration is evaluated for the three substances with a view to incorporating QSPR-predicted penetration parameters in the PBTK model when experimental values are lacking. Finally, PBTK modelling is used, first to extrapolate oral NOAEL doses derived from rat studies to humans, and then to simulate internal systemic/liver concentrations - Area Under Curve (AUC) and peak concentration - resulting from specified dermal and oral exposure conditions. Based on these simulations, AUC-based dermal thresholds for the three case study compounds are derived and compared with the experimentally obtained oral threshold (NOAEL) values.