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

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

PACEMweb: a tool for aggregate consumer exposure assessment.

BACKGROUND: To ascertain the safe use of chemicals that are used in multiple consumer products, the aggregate human exposure, arising from combined use of multiple consumer products needs to be assessed. OBJECTIVE: In this work the Probabilistic Aggregate Consumer Exposure Model (PACEM) is presented and discussed. PACEM is implemented in the publicly available web tool, PACEMweb, for aggregate consumer exposure assessment. METHODS: PACEM uses a person-oriented simulation method that is based on realistic product usage information obtained in surveys from several European countries. PACEM evaluates aggregate exposure in a population considering individual use and co-use patterns as well as variation in product composition. Product usage data is included on personal care products (PCPs) and household cleaning products (HCPs). RESULTS: PACEM has been implemented in a web tool that supports broad use in research as well as regulatory risk assessment. PACEM has been evaluated in a number of applications, testing and illustrating the advantage of the person-oriented modeling method. Also, PACEM assessments have been evaluated by comparing its results with biomonitoring information. SIGNIFICANCE: PACEM enables the assessment of realistic aggregate exposure to chemicals in consumer products. It provides detailed insight into the distribution of exposure in a population as well as products that contribute the most to exposure. This allows for better informed decision making in the risk management of chemicals. IMPACT: Realistic assessment of the total, aggregate exposure of consumers to chemicals in consumer products is necessary to guarantee the safe use of chemicals in these products. PACEMweb provides, for the first time, a publicly available tool to assist in realistic aggregate exposure assessment of consumers to chemicals in consumer products.

Challenges in Predicting the Change in the Cumulative Exposure of New Tobacco and Related Products Based on Emissions and Toxicity Dose-Response Data.

Many novel tobacco products have been developed in recent years. Although many may emit lower levels of several toxicants, their risk in the long term remains unclear. We previously published a method for the exposure assessment of mixtures that can be used to compare the changes in cumulative exposure to carcinogens among tobacco products. While further developing this method by including more carcinogens or to explore its application to non-cancer endpoints, we encountered a lack of data that are required for better-substantiated conclusions regarding differences in exposure between products. In this special communication, we argue the case for more data on adverse health effects, as well as more data on the composition of the emissions from tobacco products. Such information can be used to identify significant changes in relevance to health using the cumulative exposure method with different products and to substantiate regulatory decisions.

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

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

Combined Exposure to Multiple Mycotoxins: An Example of Using a Tiered Approach in a Mixture Risk Assessment.

Humans are exposed to mycotoxins on a regular basis. Exposure to a mixture of mycotoxins may, therefore, result in a combination of adverse effects, or trigger the same effects. This should be accounted for when assessing the combined risk of multiple mycotoxins. Here, we show the outcome of using different approaches in assessing the risks related to the combined exposure to mycotoxins. We performed a tiered approach using assessment groups with a common target organ (kidney, liver and haematologic system), or a common adverse effect (phenomenon) (reduced white blood cell count), to combine the exposure to mycotoxins. The combined exposure was calculated for the individuals in this assessment, using the Monte Carlo Risk Assessment (MCRA) tool. The risk related to this combined exposure was assessed using toxicological reference values, e.g., health based guidance values. We show that estimating the combined risk by adding the single compounds' risk distributions slightly overestimates the combined risk in the 95th percentile, as compared to combining the exposures at an individual level. We also show that relative potency factors can be used to refine the mixture risk assessment, as compared to ratios of toxicological reference values with different effect sizes and assessment factors.

Quantitative chemical risk assessment for mixtures: Application to alkylphenol mixtures and phthalate mixtures in tap and bottled water.

The occurrence and hazard risks of mixtures of Contaminants of Emerging Concern (CECs) in drinking water (DW) lead to serious consideration regarding the possible impacts on public health. Consequently, there is ongoing research, development and empowerment of risk assessment procedures to get more toxicological insight. For instance, alkylphenols and phthalates have been frequently reported to be present both in bottled and tap water, affecting different human endpoints. Currently, deterministic chemical risk assessment (CRA) is used to evaluate the compounds' mixture health risk. However, CRA deals just qualitatively with sources of uncertainty, which may lead to erroneous assessment of risks. Here, a new procedure for quantitative chemical risk assessment of CEC mixtures (QCRAMIX) is proposed. Its potential is illustrated by a case study where the risks related to the presence of mixtures of alkylphenols or phthalates in tap versus bottled DW are compared. Uncertainties in both exposure and hazard assessment steps of the procedure are included to calculate a probabilistic mixture Benchmark Quotient (BQMIX). The QCRAMIX procedure highlighted the non-negligible health risks posed by those compounds in both DW sources based on overall water consumption. In fact, DW consumers' behaviour in 13 different countries, in terms of total DW consumption and fraction of bottled and tap water consumed, were considered to evaluate the influence on health risk. For alkylphenols, the total water consumption was found to be the most relevant factor in increasing the health risk, while for phthalates the risk was found to be mainly influenced by the percentage of bottled water consumed. Hence, the proposed QCRAMIX procedure can be a valuable tool for prioritization of CECs to be included in DW regulations which aim to minimize the overall risk, accounting for actual DW consumption.

Development of a quantitative chemical risk assessment (QCRA) procedure for contaminants of emerging concern in drinking water supply.

The uncertainties on the occurrence, fate and hazard of Contaminants of Emerging Concern (CECs) increasingly challenge drinking water (DW) utilities whether additional measures should be taken to reduce the health risk. This has led to the development and evaluation of risk-based approaches by the scientific community. DW guideline values are commonly derived based on deterministic chemical risk assessment (CRA). Here, we propose a new probabilistic procedure, that is a quantitative chemical risk assessment (QCRA), to assess potential health risk related to the occurrence of CECs in DW. The QCRA includes uncertainties in risk calculation in both exposure and hazard assessments. To quantify the health risk in terms of the benchmark quotient probabilistic distribution, the QCRA estimates the probabilistic distribution of CECs concentration in DW based on their concentration in source water and simulating the breakthrough curves of a granular activated carbon (GAC) treatment process. The model inputs and output uncertainties were evaluated by sensitivity and uncertainty analyses for each step of the risk assessment to identify the most relevant factors affecting risk estimation. Dominant factors resulted to be the concentration of CECs in water sources, GAC isotherm parameters and toxicological data. To stress the potential of this new QCRA approach, several case studies are considered with focus on bisphenol A as an example CEC and various GAC management options. QCRA quantifies the probabilistic risk, providing more insight compared to CRA. QCRA proved to be more effective in supporting the intervention prioritization for treatment optimization to pursue health risk minimization.

Pulmonary toxicity and gene expression changes after short-term inhalation exposure to surface-modified copper oxide nanoparticles.

Copper oxide nanoparticles (CuO NPs) have previously been shown to cause dose-dependent pulmonary toxicity following inhalation. Here, CuO NPs (10 nm), coated with polyethylenimine (PEI) or ascorbate (ASC) resulting in positively or negatively charged NPs, respectively, were evaluated. Rats were exposed nose-only to similar exposure dose levels of ASC or PEI coated CuO NPs for 5 consecutive days. On day 6 and day 27 post-exposure, pulmonary toxicity markers in bronchoalveolar lavage fluid (BALF), lung histopathology and genome-wide transcriptomic changes in lungs, were assessed. BALF analyses showed a dose-dependent pulmonary inflammation and cell damage, which was supported by the lung histopathological findings of hypertrophy/hyperplasia of bronchiolar and alveolar epithelium, interstitial and alveolar inflammation, and paracortical histiocytosis in mediastinal lymph nodes for both types of CuO NPs. Transcriptomics analysis showed that pathways related to inflammation and cell proliferation were significantly activated. Additionally, we found evidence for the dysregulation of drug metabolism-related genes, especially in rats exposed to ASC-coated CuO NPs. Overall, no differences in the type of toxic effects and potency between the two surface coatings could be established, except with respect to the (regional) dose that initiates bronchiolar and alveolar hypertrophy. This disproves our hypothesis that differences in surface coatings affect the pulmonary toxicity of CuO NPs.

Culture Conditions Affect Chemical-Induced Developmental Toxicity In Vitro: The Case of Folic Acid, Methionine and Methotrexate in the Neural Embryonic Stem Cell Test.

In vitro tests are increasingly applied in chemical hazard assessment. Basic culture conditions may affect the outcome of in vitro tests and should be optimised to reduce false predictions. The neural embryonic stem cell test (ESTn) can predict early neurodevelopmental effects of chemicals, as it mimics the differentiation of stem cells towards the neuroectodermal lineage. Normal early neural differentiation depends crucially on folic acid (FA) and methionine (MET), both elements of the one-carbon (1C) cycle. The aim of this study was to assess the concentration-dependent influence of FA and MET on neural differentiation in the ESTn, and its consequences for assay sensitivity to methotrexate (MTX), a compound that interferes with the 1C cycle. Neural differentiation was inhibited below 0.007 mM and above 0.22 mM FA, while both stem cell viability (< 0.097 mM, > 1.52 mM) and neural differentiation (< 0.181 mM, > 1.35 mM) were affected when changing MET concentrations. A 10-day exposure to 13 nM MTX inhibited neural differentiation, especially in FA- and MET-deficient conditions. However, a 24-hour exposure to 39 nM MTX decreased neural cell and neural crest cell differentiation markers only when the concentration of FA in the medium was three times the standard concentration, which was expected to have a protective effect against MTX. These results show the importance of nutrient concentrations, exposure scenarios and timing of read-outs for cell differentiation and compound sensitivity in the ESTn. Caution should be taken when interpreting results from a single in vitro test, especially when extrapolating to effects on complex morphogenetic processes, like neural tube development.

Probabilistic approach for assessing cancer risk due to benzo[a]pyrene in barbecued meat: Informing advice for population groups.

BACKGROUND: Consumption of meat prepared by barbecuing is associated with risk of cancer due to formation of carcinogenic compounds including benzo[a]pyrene (BaP). Assessment of a population's risk of disease and people's individual probability of disease given specific consumer attributes may direct food safety strategies to where impact on public health is largest. The aim of this study was to propose a model that estimates the risk of cancer caused by exposure to BaP from barbecued meat in Denmark, and to estimate the probability of developing cancer in subgroups of the population given different barbecuing frequencies. METHODS: We developed probabilistic models applying two dimensional Monte Carlo simulation to take into account the variation in exposure given age and sex and in the individuals' sensitivity to develop cancer after exposure to BaP, and the uncertainty in the dose response model. We used the Danish dietary consumption survey, monitoring data of chemical concentrations, data on consumer behavior of frequency of barbecuing, and animal dose response data. FINDINGS: We estimated an average extra lifetime risk of cancer due to BaP from barbecued meat of 6.8 × 10-5 (95% uncertainty interval 2.6 × 10-7 - 7.0 × 10-4) in the Danish population. This corresponds to approximately one to 4,074 extra cancer cases over a lifetime, reflecting wide uncertainty. The impact per barbecuing event on the risk of cancer for men and women of low body weight was higher compared to higher bodyweight. However, the difference due to sex and bodyweight between subgroups are dwarfed by the uncertainty. INTERPRETATION: This study proposes a model that can be applied to other substances and routes of exposure, and allows for deriving the change in risk following a specific change in behaviour. The presented methodology can serve as a valuable tool for risk management, allowing for the formulation of behaviour advice targeted to specific sub-groups in the population.

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

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

APROBA-Plus: A probabilistic tool to evaluate and express uncertainty in hazard characterization and exposure assessment of substances.

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.

Organ burden and pulmonary toxicity of nano-sized copper (II) oxide particles after short-term inhalation exposure.

INTRODUCTION: Increased use of nanomaterials has raised concerns about the potential for undesirable human health and environmental effects. Releases into the air may occur and, therefore, the inhalation route is of specific interest. Here we tested copper oxide nanoparticles (CuO NPs) after repeated inhalation as hazard data for this material and exposure route is currently lacking for risk assessment. METHODS: Rats were exposed nose-only to a single exposure concentration and by varying the exposure time, different dose levels were obtained (C × T protocol). The dose is expressed as 6 h-concentration equivalents of 0, 0.6, 2.4, 3.3, 6.3, and 13.2 mg/m(3) CuO NPs, with a primary particle size of 10 9.2-14 nm and an MMAD of 1.5 µm. RESULTS: Twenty-four hours after a 5-d exposure, dose-dependent lung inflammation and cytotoxicity were observed. Histopathological examinations indicated alveolitis, bronchiolitis, vacuolation of the respiratory epithelium, and emphysema in the lung starting at 2.4 mg/m(3). After a recovery period of 22 d, limited inflammation was still observed, but only at the highest dose of 13.2 mg/m(3). The olfactory epithelium in the nose degenerated 24 h after exposure to 6.3 and 13.2 mg/m(3), but this was restored after 22 d. No histopathological changes were detected in the brain, olfactory bulb, spleen, kidney and liver. CONCLUSION: A 5-d, 6-h/day exposure equivalent to an aerosol of agglomerated CuO NPs resulted in a dose-dependent toxicity in rats, which almost completely resolved during a 3-week post-exposure period.

The probabilistic aggregate consumer exposure model (PACEM): validation and comparison to a lower-tier assessment for the cyclic siloxane D5.

Current practice of chemical risk assessment for consumer product ingredients still rarely exercises the aggregation of multi-source exposure. However, focusing on a single dominant source/pathway combination may lead to a significant underestimation of the risk for substances present in numerous consumer products, which often are used simultaneously. Moreover, in most cases complex multi-route exposure scenarios also need to be accounted for. This paper introduces and evaluates the performance of the Probabilistic Aggregate Consumer Exposure Model (PACEM) applied in the context of a tiered approach to exposure assessment for ingredients in cosmetics and personal care products (C&PCPs) using decamethylcyclopentasiloxane (D5) as a worked example. It is demonstrated that PACEM predicts a more realistic, but still conservative aggregate exposure within the Dutch adult population when compared to a deterministic point estimate obtained in a lower tier screening assessment. An overall validation of PACEM is performed by quantitatively relating and comparing its estimates to currently available human biomonitoring and environmental sampling data. Moderate (by maximum one order of magnitude) overestimation of exposure is observed due to a justified conservatism built into the model structure, resulting in the tool being suitable for risk assessment.

Exploring the uncertainties in cancer risk assessment using the integrated probabilistic risk assessment (IPRA) approach.

Current methods for cancer risk assessment result in single values, without any quantitative information on the uncertainties in these values. Therefore, single risk values could easily be overinterpreted. In this study, we discuss a full probabilistic cancer risk assessment approach in which all the generally recognized uncertainties in both exposure and hazard assessment are quantitatively characterized and probabilistically evaluated, resulting in a confidence interval for the final risk estimate. The methodology is applied to three example chemicals (aflatoxin, N-nitrosodimethylamine, and methyleugenol). These examples illustrate that the uncertainty in a cancer risk estimate may be huge, making single value estimates of cancer risk meaningless. Further, a risk based on linear extrapolation tends to be lower than the upper 95% confidence limit of a probabilistic risk estimate, and in that sense it is not conservative. Our conceptual analysis showed that there are two possible basic approaches for cancer risk assessment, depending on the interpretation of the dose-incidence data measured in animals. However, it remains unclear which of the two interpretations is the more adequate one, adding an additional uncertainty to the already huge confidence intervals for cancer risk estimates.

Comparative hazard identification of nano- and micro-sized cerium oxide particles based on 28-day inhalation studies in rats.

There are many uncertainties regarding the hazard of nanosized particles compared to the bulk material of the parent chemical. Here, the authors assess the comparative hazard of two nanoscale (NM-211 and NM-212) and one microscale (NM-213) cerium oxide materials in 28-day inhalation toxicity studies in rats (according to Organisation for Economic Co-operation and Development technical guidelines). All three materials gave rise to a dose-dependent pulmonary inflammation and lung cell damage but without gross pathological changes immediately after exposure. Following NM-211 and NM-212 exposure, epithelial cell injury was observed in the recovery groups. There was no evidence of systemic inflammation or other haematological changes following exposure of any of the three particle types. The comparative hazard was quantified by application of the benchmark concentration approach. The relative toxicity was explored in terms of three exposure metrics. When exposure levels were expressed as mass concentration, nanosized NM-211 was the most potent material, whereas when expression levels were based on surface area concentration, micro-sized NM-213 material induced the greatest extent of pulmonary inflammation/damage. Particles were equipotent based on particle number concentrations. In conclusion, similar pulmonary toxicity profiles including inflammation are observed for all three materials with little quantitative differences. Systemic effects were virtually absent. There is little evidence for a dominant predicting exposure metric for the observed effects.

Presence and risks of nanosilica in food products.

This study uniquely describes all steps of the risk assessment process for the use of one specific nanomaterial (nanosilica) in food products. The aim was to identify gaps in essential knowledge and the difficulties and uncertainties associated with each of these steps. Several food products with added silica (E551) were analyzed for the presence, particle size and concentration of nanosilica particles, using experimental analytical data, and the intake of nanosilica via food was estimated. As no information is available on the absorption of nanosilica from the gastrointestinal tract, two scenarios for risk assessment were considered. The first scenario assumes that the silica is absorbed as dissolved silica, while the second scenario assumes that nanosilica particles themselves are absorbed from the gastrointestinal tract. For the first scenario no adverse effects are expected to occur. For the second scenario there are too many uncertainties to allow proper risk assessment. Therefore, it is recommended to prioritize research on how nanosilica is absorbed from the gastrointestinal tract.

Comparison of two models for the estimation of usual intake addressing zero consumption and non-normality.

Various models exist for estimating the usual intake distribution from dietary intake data. In this paper, we compare two of these models, the Iowa State University Foods (ISUF) model and the betabinomial-normal (BBN) model and apply them to three different datasets. Intake data are obtained by aggregating over multiple food products and are often non-normal. The ISUF and BBN model both address non-normality. While the two models have similar structures, they show some differences. The ISUF model includes an additional spline transformation for improving the normality of the intake amount distribution, while the BBN model includes the possibility of addressing covariates, such as age or sex. Our analyses showed that for two of the example datasets both models produced similar estimates of the higher percentiles of the usual intake distribution. However, for the third dataset, where the intake amount distribution appear to be multimodal, both models produced different percentile estimates.

Deriving a data-based interspecies assessment factor using the NOAEL and the benchmark dose approach.

In deriving human health-based exposure limits from animal data, differences in sensitivity to a compound between animals and humans must be taken into account. These interspecies differences can be caused by differences in toxicokinetics and or toxicodynamics. Apart from that, species differ in body size, and this is usually accounted for by scaling doses to body weight (i.e., expressed as mg/kg body weight1.0/day). Adefault assessmentfactor (AF) of 10 is commonly applied to this dose metric to account for potential toxicokinetic and toxicodynamic differences. However, both proportional body weight (BW)scalingand the defaultAFas often applied are not directly based on empirical findings. Attempts have been made to derive data-based assessment factors and allometric scaling powers using various toxicological values such as no-observedadverse-effect-levels (NOAELs). In thisstudy both the NOAEL approach and the benchmark dose (BMD) approach are applied to deriveNOAEL ratios and BMD ratios from mouse and rat studies and, based on that information, toestimate an allometric scaling power and an interspecies AF. To account for interspecies differences in body size, our results confirm earlier findings that allometric body weight scaling with a power of around 0.7 is appropriate. The factor needed to rescale the dose in terms of mg/kgBWto the allometric dose scale ranges from around 1.7 (for dogs) to 10(for mice), similar to other findings. The additional factor required for taking into account interspecies toxicokinetic and toxicodynamic differences, when based on the 95th percentile of the relevant ratio distribution, would be 3.1 for a lower Confidence limit of theBMD (BMDL), and 8.3 for a NOAEL (to be applied to the allometrically scaled dose). These results indicate that the generally used defaultAFof 10 may not cover potential interspecies differences, in particular when applied to results from smaller test species. Therefore, using the default AF of 10 could lead to human exposure limits that are insufficiently protective. Further, our results show that a data-based AF that would be needed for interspecies extrapolation is smaller when the point of departure is aBMDLrather than a NOAEL. In the context of a probabilistic hazard characterization, our results indicate that the (geometric) SD of the interspecies AF distribution should be around 2.0 when the BMDL (or BMD uncertainty distribution) is used, and around 3.4 when the NOAEL is used as a point of departure for further risk assessment.

A comparison of ratio distributions based on the NOAEL and the benchmark approach for subchronic-to-chronic extrapolation.

One approach to derive a data-based assessment factor (AF) for subchronic-to-chronic extrapolation is to determine ratios between the NOAEL(subchronic) and NOAEL(chronic) for the same compounds. Instead of using ratios of NOAELs, the distribution can also be estimated by ratios of subchronic and chronic Benchmark Doses (or Critical Effect Doses, CEDs, for continuous data). In this study 314 dose-response datasets on body weights and liver weights of mice and rats were selected providing dose-response information after both subchronic and chronic exposure. NOAEL ratios could be derived in only 68 of these datasets, while CED ratios could be derived in 189 datasets. When only the (53) datasets suitable for both approaches were evaluated the variation of the CED ratio distribution (GSD [geometric standard deviation]: 2.9) was smaller than the one of the NOAEL ratio distribution (GSD: 3.3). After correcting for the estimation error of the individual CED ratios the GSD of the CED distribution decreased to 2.3. The geometric means (GMs) of the NOAEL and CED distributions were similar (1.2 and 1.6, respectively). Comparing the NOAEL distribution based on all 68 datasets suitable for deriving NOAEL ratios with the CED distribution based on the 189 ratios suitable for deriving CED ratios resulted in similar GMs (1.5 and 1.7, respectively), but the GSDs differed considerably (5.3 and 2.3 respectively). It is concluded that usage of the CED approach results in less wide distributions. Furthermore, a larger fraction of available datasets is useful to inform the ratio distribution. This results in more accurate, and less conservative distributions of AFs in general compared to the distributions based on NOAEL ratios that have been proposed so far.