Benchmark Dose Approach Research Articles

A method of identifying health-based benchmarks for psychosocial risks at work: A tool for risk assessment

ObjectivesWe present a novel approach to identify critical exposure levels or health-based benchmarks of job control using the benchmark dose (BMD) method. This method provides benchmarks for risk assessment of psychosocial risks, similar to benchmarks used for other occupational health hazards such as chemicals. MethodsTwo staged (bivariate and adjusted) BMD modelling was conducted using epidemiological data from an age-cohort study in south-eastern Australia. The adjusted BMD model incorporated age, gender, education, personality traits and mental health status at baseline. ResultsDepression is a more sensitive (health compromising) outcome for job control compared to anxiety in both types of BMD modelling. For an excess risk of 5% for depression, the adjusted benchmark dose was 0.49 and the critical exposure level, being the lower one sided 95% confidence limit of the adjusted BMD, was 0.37. If workplace guidelines are based on this critical exposure level, workers need to have a minimum of ten out of 15 aspects of job control measured in this study to reduce the excess risk of depression. ConclusionsThe BMD approach can identify critical exposure levels for job control. This suggests a similar approach can be used for other psychosocial risks for which no critical exposure levels are currently available. Critical exposure levels can provide guidance needed to assess risk and address psychosocial risks, similar to other health hazards. Benchmarks or critical exposure levels of psychosocial risks can assist the inspectorate and employers to conduct risk assessment of workplaces and identify areas for intervention.

Maternal-Fetal Cancer Risk Assessment of Ochratoxin A during Pregnancy.

Increasing evidence has demonstrated that in utero exposure to environmental chemicals may interfere with fetal development and increase the risk of disease and cancer development later in life. Ochratoxin A (OTA) has been proven to induce diverse toxic effects including teratogenicity, carcinogenicity, immunotoxicity and potential endocrine disruption. Due to the continuous and widespread occurrence of OTA as a potential contaminant of staple foods, there is increasing concern of in utero exposure of fetus to this mycotoxin. In this study, maternal-fetal risk assessment of OTA during pregnancy was conducted using the benchmark dose approach for genotoxic carcinogens. The daily intake of OTA for Egyptian pregnant women was estimated based on their serum OTA level using the refined Klaassen equation for pregnancy. Fetal exposure level was also estimated based on the maternal data. Comparison between the estimated daily exposure and the negligible cancer risk intake (NCRI), and the calculation of margin of exposure (MOE) implicated that OTA exposure from dietary intake would be of low health concern for this general subpopulation of Egyptian women. This subpopulation of pregnant women was generally estimated not to be in high-risk for toxicity induced by OTA.

Genetic toxicology at the crossroads-from qualitative hazard evaluation to quantitative risk assessment.

Applied genetic toxicology is undergoing a transition from qualitative hazard identification to quantitative dose-response analysis and risk assessment. To facilitate this change, the Health and Environmental Sciences Institute (HESI) Genetic Toxicology Technical Committee (GTTC) sponsored a workshop held in Lancaster, UK on July 10-11, 2014. The event included invited speakers from several institutions and the contents was divided into three themes-1: Point-of-departure Metrics for Quantitative Dose-Response Analysis in Genetic Toxicology; 2: Measurement and Estimation of Exposures for Better Extrapolation to Humans and 3: The Use of Quantitative Approaches in Genetic Toxicology for human health risk assessment (HHRA). A host of pertinent issues were discussed relating to the use of in vitro and in vivo dose-response data, the development of methods for in vitro to in vivo extrapolation and approaches to use in vivo dose-response data to determine human exposure limits for regulatory evaluations and decision-making. This Special Issue, which was inspired by the workshop, contains a series of papers that collectively address topics related to the aforementioned themes. The Issue includes contributions that collectively evaluate, describe and discuss in silico, in vitro, in vivo and statistical approaches that are facilitating the shift from qualitative hazard evaluation to quantitative risk assessment. The use and application of the benchmark dose approach was a central theme in many of the workshop presentations and discussions, and the Special Issue includes several contributions that outline novel applications for the analysis and interpretation of genetic toxicity data. Although the contents of the Special Issue constitutes an important step towards the adoption of quantitative methods for regulatory assessment of genetic toxicity, formal acceptance of quantitative methods for HHRA and regulatory decision-making will require consensus regarding the relationships between genetic damage and disease, and the concomitant ability to use genetic toxicity results per se.

Empirical analysis of BMD metrics in genetic toxicology part II: in vivo potency comparisons to promote reductions in the use of experimental animals for genetic toxicity assessment.

Genotoxicity tests have traditionally been used only for hazard identification, with qualitative dichotomous groupings being used to identify compounds that have the capacity to induce mutations and/or cytogenetic alterations. However, there is an increasing interest in employing quantitative analysis of in vivo dose-response data to derive point of departure (PoD) metrics that can be used to establish human exposure limits or margins of exposure (MOEs), thereby supporting human health risk assessments and regulatory decisions. This work is an extension of our companion article on in vitro dose-response analyses and outlines how the combined benchmark dose (BMD) approach across included covariates can be used to improve the analyses and interpretation of in vivo genetic toxicity dose-response data. Using the BMD-covariate approach, we show that empirical comparisons of micronucleus frequency dose-response data across multiple studies justifies dataset merging, with subsequent analyses improving the precision of BMD estimates and permitting attendant potency ranking of seven clastogens. Similarly, empirical comparisons of Pig-a mutant phenotype frequency data collected in males and females justified dataset merging across sex. This permitted more effective scrutiny regarding the effect of post-exposure sampling time on the mutagenicity of N-ethyl-N-nitrosourea observed in reticulocytes and erythrocytes in the Pig-a assay. The BMD-covariate approach revealed tissue-specific differences in the induction of lacZ transgene mutations in Muta™Mouse specimens exposed to benzo[a]pyrene (BaP), with the results permitting the formulation of mechanistic hypotheses regarding the observed potency ranking. Lastly, we illustrate how historical dose-response data for assessments that examined numerous doses (i.e. induced lacZ mutant frequency (MF) across 10 doses of BaP) can be used to improve the precision of BMDs derived from datasets with far fewer doses (i.e. lacZ MF for 3 doses of dibenz[a,h]anthracene). Collectively, the presented examples illustrate how innovative use of the BMD approach can permit refinement of the use of in vivo data; improving the efficacy of experimental animal use in genetic toxicology without sacrificing PoD precision.

Probe on the biomarker to substitute the dental fluorosis for deriving fluoride threshold by animal study

Dental fluorosis had been used for deriving the fluoride acceptable threshold for a long time. However, it was diagnosed on the color or defect degree of tooth, like Dean’s Index, which would be easily influenced by lifestyle, like smoking and drinking tea. Hence, some biomarkers had already tried to assess the fluoride exposure risk with the development of bio-monitor technique, and this paper probed on an available biomarker, which based on a systematic biochemical indicator group relating to different biological function from animal experiment, to take place the old one. The experiment animals had been treated with different levels of NaF, and biochemical indicators were analyzed after three months later. The correlations between changes of biochemical indicators and the exposure levels were analyzed subsequently, and a comprehensive indicator was developed. Both the NOAEL/LOAEL and the Benchmark Dose approach were applied in this article to derive the suitable threshold and for indicator comparison. Our findings indicated that a better dose-response relationship was shown between the comprehensive indicator and exposure dose (R=0.811, R square=0.657) than single indicator (R<0.4, R square<0.2) and Dean’s Index (R=0.737, R square= 0.543). Furthermore, the available threshold of the comprehensive indicator was 1.70 mg/(kg.d) lower than it from dental fluorosis (2.00 mg/(kg.d)) which can protect animals from fluoride damage at rather low exposure level. Even the scientificity of the comprehensive indicator should be verified in further epidemiology research, its advantage can’t be ignored that it cannot only avoid the personally error during clinical diagnosis, but also present a new method to quantize the gap risk from dental fluorosis to skeletal fluorosis for those people cannot be diagnosed by dental fluorosis clinically.

Empirical analysis of BMD metrics in genetic toxicology part I: in vitro analyses to provide robust potency rankings and support MOA determinations.

Genetic toxicity testing has traditionally been used for hazard identification, with dichotomous classification of test results serving to identify genotoxic agents. However, the utility of genotoxicity data can be augmented by employing dose-response analysis and point of departure determination. Via interpolation from a fitted dose-response model, the benchmark dose (BMD) approach estimates the dose that elicits a specified (small) effect size. BMD metrics and their confidence intervals can be used for compound potency ranking within an endpoint, as well as potency comparisons across other factors such as cell line or exposure duration. A recently developed computational method, the BMD covariate approach, permits combined analysis of multiple dose-response data sets that are differentiated by covariates such as compound, cell type or exposure regime. The approach provides increased BMD precision for effective potency rankings across compounds and other covariates that pertain to a hypothesised mode of action (MOA). To illustrate these applications, the covariate approach was applied to the analysis of published in vitro micronucleus frequency dose-response data for ionising radiations, a set of aneugens, two mutagenic azo compounds and a topoisomerase II inhibitor. The ionising radiation results show that the precision of BMD estimates can be improved by employing the covariate method. The aneugen analysis provided potency groupings based on the BMD confidence intervals, and analyses of azo compound data from cells lines with differing metabolic capacity confirmed the influence of endogenous metabolism on genotoxic potency. This work, which is the first of a two-part series, shows that BMD-derived potency rankings can be employed to support MOA evaluations as well as facilitate read across to expedite chemical evaluations and regulatory decision-making. The follow-up (Part II) employs the combined covariate approach to analyse in vivo genetic toxicity dose-response data focussing on how improvements in BMD precision can impact the reduction and refinement of animal use in toxicological research.

Oxidative stress and renal toxicity after subacute exposure to decabrominated diphenyl ether in Wistar rats.

Fully brominated diphenyl ether (BDE-209) is a flame retardant widely used in plastics and textiles. Because of its high persistence, humans are exposed to it continuously, mainly via dust ingestion. We investigated effects of BDE-209 on renal function and oxidative stress development in the kidney after subacute exposure in rats. Five groups of animals were given by oral gavage 31.25-500mg BDE-209/kg b.w./day for 28days, and relative kidney weight, serum urea and creatinine, and oxidative stress parameters in the kidney were determined. Benchmark-dose approach was used for dose response modeling. Serum creatinine was increased, while results obtained for serum urea were inconclusive. Relative kidney weight was not affected by BDE-209. Kidney reduced glutathione was elevated, while superoxide dismutase activity was not changed after BDE-209 treatment. Also, levels of thiobarbituric acid reactive substances (TBARS) were increased and total -SH groups were decreased, which indicated oxidative imbalance. The critical effect dose (CED)/CEDL ratios for the effects on TBARS and total -SH groups indicated estimated CEDs for these markers can be used in risk assessment of BDE-209. Our study results have shown that a relatively low dose of BDE-209 affects kidney function and that oxidative stress is one of the mechanisms of its nephrotoxicity.

Qualitative and quantitative approaches in the dose-response assessment of genotoxic carcinogens.

Qualitative and quantitative approaches are important issues in field of carcinogenic risk assessment of the genotoxic carcinogens. Herein, we provide quantitative data on low-dose hepatocarcinogenicity studies for three genotoxic hepatocarcinogens: 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and N-nitrosodiethylamine (DEN). Hepatocarcinogenicity was examined by quantitative analysis of glutathione S-transferase placental form (GST-P) positive foci, which are the preneoplastic lesions in rat hepatocarcinogenesis and the endpoint carcinogenic marker in the rat liver medium-term carcinogenicity bioassay. We also examined DNA damage and gene mutations which occurred through the initiation stage of carcinogenesis. For the establishment of points of departure (PoD) from which the cancer-related risk can be estimated, we analyzed the above events by quantitative no-observed-effect level and benchmark dose approaches. MeIQx at low doses induced formation of DNA-MeIQx adducts; somewhat higher doses caused elevation of 8-hydroxy-2'-deoxyquanosine levels; at still higher doses gene mutations occurred; and the highest dose induced formation of GST-P positive foci. These data indicate that early genotoxic events in the pathway to carcinogenesis showed the expected trend of lower PoDs for earlier events in the carcinogenic process. Similarly, only the highest dose of IQ caused an increase in the number of GST-P positive foci in the liver, while IQ-DNA adduct formation was observed with low doses. Moreover, treatment with DEN at low doses had no effect on development of GST-P positive foci in the liver. These data on PoDs for the markers contribute to understand whether genotoxic carcinogens have a threshold for their carcinogenicity. The most appropriate approach to use in low dose-response assessment must be approved on the basis of scientific judgment.

Review of the state of the art of human biomonitoring for chemical substances and its application to human exposure assessment for food safety

Review of the state of the art of human biomonitoring for chemical substances and its application to human exposure assessment for food safety

Report on the two‐phase public consultation on the draft EFSA scientific opinion on bisphenol A (BPA)

Report on the two‐phase public consultation on the draft EFSA scientific opinion on bisphenol A (BPA)

Benchmark dose estimation of cadmium reference level for hypertension in a Chinese population

Cadmium exposure can cause high blood pressure or hypertension. Benchmark dose has been used to estimate the reference point of cadmium for kidney and bone damage. In this study, we observed the association of blood pressure and cadmium in blood (BCd) and evaluated the reference level of cadmium for hypertension using benchmark dose (BMD) approach. A total of 441 subjects were included in this study. Blood samples were collected from each individual for BCd determination. Blood pressure was measured by electronic sphygmomanometer. BMD and BMDL were calculated using BMD software corresponding to additional risk of 10%. The systolic blood pressure (SBP), diastolic blood pressure (DBP) and prevalence of hypertension increased with the increasing of BCd, especially for SBP (χ2=3.9, p=0.047 in men; χ2=4.3, p=0.037 in women). With a benchmark response of 10%, the BMDL10 for hypertension (high SBP) was 0.95μg/L and 1.02μg/L for women and men, respectively; the BMDL10 for hypertension (high DBP) was 1.8μg/L and 1.66μg/L for women and men, respectively. Our data evidenced that BCd was associated with elevation in blood pressure and hypertension, especially for women. The reference level of cadmium for hypertension with high SBP was lower than that of high DBP.

Interindividual variation in response to xenobiotic exposure established in precision-cut human liver slices.

Large differences in toxicity responses occur within the human population. In this study we evaluate whether interindividual variation in baseline enzyme activity (EA)/gene expression (GE) levels in liver predispose for the variation in toxicity responses by assessing dose-response relationships for several prototypical hepatotoxicants. Baseline levels of cytochrome-P450 (CYP) GE/EA were measured in precision-cut human liver slices. Slices (n=4-5/compound) were exposed to a dose-range of acetaminophen, aflatoxin B1, benzo(α) pyrene or 2-nitrofluorene. Interindividual variation in induced genotoxicity (COMET-assay and CDKN1A/p21 GE) and cytotoxicity (lactate dehydrogenase-leakage), combined with NQO1- and GSTM1-induced GE-responses for oxidative stress and GE-responses of several CYPs was evaluated. The benchmark dose-approach was applied as a tool to model exposure responses on an individual level. Variation in baseline CYP levels, both GE and EA, can explain variation in compound exposure-responses on an individual level. Network analyses enable the definition of key parameters influencing interindividual variation after compound exposure. For 2-nitrofluorene, this analysis suggests involvement of CYP1B1 in the metabolism of this compound, which represents a novel finding. In this study, GSTM1 which is known to be highly polymorphic within the human population, but so far could not be linked to toxicity in acetaminophen-poisoned patients, is suggested to cause interindividual variability in acetaminophen-metabolism, dependent on the individual's gene expression-responses of CYP-enzymes. This study demonstrates that using interindividual variation within network modelling provides a source for the definition of essential and even new parameters involved in compound-related metabolism. This information might enable ways to make more quantitative estimates of human risks.

Application of BMD Approach to Identify Thresholds of Cadmium-Induced Renal Effect among 35 to 55 Year-Old Women in Two Cadmium Polluted Counties in China

BackgroundCadmium (Cd) is a heavy metal that can cause renal tubular dysfunction in humans. Women are among the high-risk group for Cd health effects. Determining the thresholds of Cd-induced renal effects is important. Thus, in this article, we aimed to identify the benchmark dose (BMD) and its low limit (BMDL) levels as the Cd thresholds for Chinese women.MethodsEpidemiologic investigation was performed in county A and county B to obtain data on Cd exposure and its renal effect on respondents. Levels of Cd (UCd), β2-microglobulin (UB2M), and N-acetyl-β-D-glucosaminidase (UNAG) were measured in morning urine samples. The BMD approach was mainly performed.ResultsResults of the BMD approach were similar whether the method was conducted for the two sets of data (collected in CA and CB, respectively) separately or cooperatively. The BMD/BMDL values of UCd for all subjects were 1.07/0.44 and 2.12/0.53 µg/g cr based on UB2M and UNAG, respectively, given a predetermined BMR of 0.05.ConclusionsThe presented thresholds of Cd-induced renal effects (i.e., the BMDLs of UCd) are close to the counterpart values reported in Japan, Sweden and Belguim.

Mode of action analysis for liver tumors from oral 1,4-dioxane exposures and evidence-based dose response assessment

1,4-Dioxane is found in consumer products and is used as a solvent in manufacturing. Studies in rodents show liver tumors to be consistently reported after chronic oral exposure. However, there were differences in the reporting of non-neoplastic lesions in the livers of rats and mice. In order to clarify these differences, a reread of mouse liver slides from the 1978 NCI bioassay on 1,4-dioxane in drinking water was conducted. This reread clearly identified dose-related non-neoplastic changes in the liver; specifically, a dose-related increase in the hypertrophic response of hepatocytes, followed by necrosis, inflammation and hyperplastic hepatocellular foci. 1,4-Dioxane does not cause point mutations, DNA repair, or initiation. However, it appears to promote tumors and stimulate DNA synthesis. Using EPA Guidelines (2005), the weight of the evidence suggests that 1,4-dioxane causes liver tumors in rats and mice through cytotoxicity followed by regenerative hyperplasia. Specific key events in this mode of action are identified. A Reference Dose (RfD) of 0.05mg/kgday is proposed to protect against regenerative liver hyperplasia based on a benchmark dose (BMD) approach. Based on this RfD, a maximum contaminant level goal of 350μg/L is proposed using a default relative source contribution for water of 20%.

Benchmark Dose Calculation for Ordered Categorical Responses

The use of benchmark dose (BMD) calculations for dichotomous or continuous responses is well established in the risk assessment of cancer and noncancer endpoints. In some cases, responses to exposure are categorized in terms of ordinal severity effects such as none, mild, adverse, and severe. Such responses can be assessed using categorical regression (CATREG) analysis. However, while CATREG has been employed to compare the benchmark approach and the no-adverse-effect-level (NOAEL) approach in determining a reference dose, the utility of CATREG for risk assessment remains unclear. This study proposes a CATREG model to extend the BMD approach to ordered categorical responses by modeling severity levels as censored interval limits of a standard normal distribution. The BMD is calculated as a weighted average of the BMDs obtained at dichotomous cutoffs for each adverse severity level above the critical effect, with the weights being proportional to the reciprocal of the expected loss at the cutoff under the normal probability model. This approach provides a link between the current BMD procedures for dichotomous and continuous data. We estimate the CATREG parameters using a Markov chain Monte Carlo simulation procedure. The proposed method is demonstrated using examples of aldicarb and urethane, each with several categories of severity levels. Simulation studies comparing the BMD and BMDL (lower confidence bound on the BMD) using the proposed method to the correspondent estimates using the existing methods for dichotomous and continuous data are quite compatible; the difference is mainly dependent on the choice of cutoffs for the severity levels.

Immunotoxicity of silver nanoparticles in an intravenous 28-day repeated-dose toxicity study in rats

BackgroundNanosilver is used in a variety of medical and consumer products because of its antibacterial activity. This wide application results in an increased human exposure. Knowledge on the systemic toxicity of nanosilver is, however, relatively scarce. In a previous study, the systemic toxicity of 20 nm silver nanoparticles (Ag-NP) was studied in a 28-day repeated-dose toxicity study in rats. Ag-NP were intravenously administered with a maximum dose of 6 mg/kg body weight (bw)/day. Several immune parameters were affected: reduced thymus weight, increased spleen weight and spleen cell number, a strongly reduced NK cell activity, and reduced IFN-γ production were observed.MethodsPrompted by these affected immune parameters, we wished to assess exposure effects on the functional immune system. Therefore, in the present study the T-cell dependent antibody response (TDAR) to keyhole limpet hemocyanin (KLH) was measured in a similar 28-day intravenous repeated-dose toxicity study. In addition, a range of immunological parameters was measured. Data obtained using the benchmark dose (BMD) approach were analyzed by fitting dose-response models to the parameters measured.ResultsA reduction in KLH-specific IgG was seen, with a lowest 5% lower confidence bound of the BMD (BMDL) of 0.40 mg/kg bw/day. This suggests that Ag-NP induce suppression of the functional immune system. Other parameters sensitive to Ag-NP exposure were in line with our previous study: a reduced thymus weight with a BMDL of 0.76 mg/kg bw/day, and an increased spleen weight, spleen cell number, and spleen cell subsets, with BMDLs between 0.36 and 1.11 mg/kg bw/day. Because the effects on the spleen are not reflected by increased KLH-specific IgG, they, however, do not suggest immune stimulation.ConclusionsIntravenous Ag-NP administration in a 28-day repeated-dose toxicity study induces suppression of the functional immune system. This finding underscores the importance to study the TDAR to evaluate immunotoxicity and not to rely solely on measuring immune cell subsets.

Does EU legislation allow the use of the Benchmark dose (BMD) approach for risk assessment?

Hazard characterisation is largely based on an approach of (statistically) comparing dose groups with the controls in order to derive points of departure such as no-observed-adverse-effect levels (NOAELs) or lowest-observed-adverse-effect levels (LOAELs). This approach suggests the absence of any relevant effect at the NOAEL. The NOAEL approach has been debated for decades. A recent Scientific Opinion by the European Food Safety Authority (EFSA) concluded that the Benchmark Dose (BMD) approach should be preferred over the NOAEL approach for deriving human (health-based) limit or guidance values. Nonetheless, the BMD approach is used infrequently within European regulatory frameworks. The reason for this may lie in legislation or guidelines requiring the use of the NOAEL approach. In this context, various EU regulatory frameworks were examined on such demands. Interestingly, no single legislation was identified containing statutory requirements in conflict with the use of the BMD approach.

Model Uncertainty and Bayesian Model Averaged Benchmark Dose Estimation for Continuous Data

The benchmark dose (BMD) approach has gained acceptance as a valuable risk assessment tool, but risk assessors still face significant challenges associated with selecting an appropriate BMD/BMDL estimate from the results of a set of acceptable dose-response models. Current approaches do not explicitly address model uncertainty, and there is an existing need to more fully inform health risk assessors in this regard. In this study, a Bayesian model averaging (BMA) BMD estimation method taking model uncertainty into account is proposed as an alternative to current BMD estimation approaches for continuous data. Using the "hybrid" method proposed by Crump, two strategies of BMA, including both "maximum likelihood estimation based" and "Markov Chain Monte Carlo based" methods, are first applied as a demonstration to calculate model averaged BMD estimates from real continuous dose-response data. The outcomes from the example data sets examined suggest that the BMA BMD estimates have higher reliability than the estimates from the individual models with highest posterior weight in terms of higher BMDL and smaller 90th percentile intervals. In addition, a simulation study is performed to evaluate the accuracy of the BMA BMD estimator. The results from the simulation study recommend that the BMA BMD estimates have smaller bias than the BMDs selected using other criteria. To further validate the BMA method, some technical issues, including the selection of models and the use of bootstrap methods for BMDL derivation, need further investigation over a more extensive, representative set of dose-response data.

Scientific Opinion on the toxicological evaluation of phenol

EFSA was asked by the German Federal Institute for Risk Assessment (BfR) to re-evaluate the TDI for phenol of 1.5 mg/kg bw/day, since this value is within the same dose range which was reported to be associated with some haematotoxic and immunotoxic effects in an oral study on phenol. The Panel comprehensively reviewed the available toxicological studies, mainly those using an oral route of exposure. The CEF experts did not consider immunotoxicity as a suitable endpoint on which to base a new TDI for phenol, given the study limitations and the lack of confirmation of phenol-induced immunotoxic effects in other studies. The Panel considered a gavage developmental toxicity study and an oral two-generation reproduction toxicity study as the two most robust toxicity studies, and performed a dose-response analysis of these data using the benchmark dose (BMD) approach. The lower 95 % confidence bound (one-sided) of the BMD, denoted BMDL, was then taken as the reference point. The lowest reference point for deriving a health based guidance value was provided by the BMDL10 of 52 mg/kg bw/day for reduced maternal body weight gain from a developmental toxicity study where rats were exposed to phenol by gavage from gestational day 6 to 16. The CEF Panel set a TDI for phenol to 0.5 mg/kg bw/day, by applying a standard uncertainty factor of 100 (for inter- and intra-species differences) to this BMDL10 value. The Panel did not assess the hazards related to the possible oxidation products of phenol, e.g. quinones/hydroquinones. Therefore, the above TDI only covers phenol. Exposure to phenol may occur via sources other than food contact materials, e.g. flavourings, smoke flavourings, traditionally smoked foods, floor waxes, cosmetics, disinfectants, etc. The European Commission may wish to take note of all these sources of exposure if setting a restriction for phenol in food contact materials.

Establishment of the cumulative margin of exposure for a group of polychlorinated biphenyl (PCB) congeners using an improved approach that accounts for both variability and uncertainty

In this study, the cumulative margin of exposure (MOE) was estimated for a group of polychlorinated biphenyls (PCBs) based on reduction of hepatic retinoids as a mode-of-action relevant toxicological endpoint. The MOE was defined as the ratio between a reference dose, derived using the benchmark dose (BMD) approach, and the estimated human dietary PCB exposure. A distribution for the cumulative MOE was established, taking into account inter- and intra-individual variability as well as uncertainty in data measurements. The cumulative MOE reflected mainly the MOE for PCB 126; other PCB congeners had little contribution to the cumulative exposure and MOE. The median of the 0.1st percentile for the cumulative MOE was about 20 for women; depending on the percentile, cumulative MOE was 2–4times higher for men compared to women. Furthermore, a relative potency factor (RPF) based approach was compared to an RPF-free approach for estimating the cumulative MOE. The RPF-free approach more completely accounts for variability and uncertainty but is more data intensive than the RPF-based approach, which can be more easily implemented in practice and allows for a use of historical data on RPFs. Consideration of the discussed approaches may contribute to improving cumulative health risk assessments.