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ECETOC Technical Report no.126: Guidance for effective use of human exposure data in risk assessment of chemicals
Abstract
This report details much of the current state-of-the-art of consumer exposure assessment data and models that can be used in chemical risk assessment, with a particular focus upon aggregate exposure assessment. Aggregate exposure considers all sources of exposure to a single chemical (e.g. hair care products, cosmetics, detergents, foods, environmental media, etc.) via all routes (oral, dermal, and inhalation). The report focuses on consumer products (not including the assessment of occupational exposure), considering the following product domains: cosmetics and personal care products, household products, food and other consumer products (such as surface coatings, adhesives, sealants, disinfectants, automotive care products, toys etc.).
Exposure assessment is, by necessity, an iterative process. If, in any tier, negligible or acceptable risk cannot be demonstrated, the assessment moves to a higher tier. The risk assessment is finished if (in any tier of the approach) it has been demonstrated that the risk for the population under consideration is negligible or acceptable, or if in the highest tier the risk is not acceptable and further refinements are not possible. This approach was proposed in the WHO/IPCS framework for risk assessment of combined exposure to multiple chemicals (Meek et al, 2011).
The report is divided into four sections.
Section One gives background on the tiered approach to exposure assessment, including aggregate exposure assessment in the consumer product domains.
Section Two provides an overview of the current exposure landscape, detailing the main data sources, models and tools that are available for chemical risk assessment in the food, cosmetics, household, and consumer products domains. Conclusions and recommendations on current opportunities for the development and provision of new tools and data are also presented based on the outcome of this landscaping exercise. This section is accompanied by a detailed spreadsheet referencing all identified data sources and tools identified for chemical exposure assessment.
Section Three presents examples of case studies of aggregate exposure to the chemicals triclosan and phenoxyethanol (PhE), outlining how current models and data can be best used for higher-tier exposure assessments. In addition, there is a literature review of the broader domain of aggregate exposure assessment, detailing other examples and approaches that exist for aggregate exposure assessment.
Section Four contains discussion and conclusions on areas of opportunity for exposure science over the next two to five years.
The key conclusions of this report are summarised as follows:
• Exposure assessments should involve an iterative process, and should be conducted using a tiered strategy, where the lowest tier (0) involves a semi-quantitative assessment of the all sources, pathways and routes contributing to aggregate exposure to a substance, the mid-tier (1) tends to be a deterministic estimate with conservative assumptions, the higher tier (2) is a more realistic estimation of population exposure with increased use of measured data using probabilistic methods, and at the highest tier (3) exposure is modelled with a person-orientated approach using raw data sets.
• Many tools and databases exist to support consumer exposure assessment, as demonstrated in the landscaping effort. Users can select the data and tools that best fit their specific situation and level of assessment.
• Most consumer exposures tools are designed to evaluate single substance, single use assessments.
• Higher tier exposure assessments require more realistic and representative data to the situation being assessed and additional understanding of data correlations.
• Subject oriented aggregate tools (PACEM, Creme Care & Cosmetics) are available that allow aggregate exposure assessment within some consumer product domains. For example, in cosmetics and personal care products, the availability of robust tools and data sets (habits and practices data with product co-use, and the use of presence probabilities) allow refined estimates of aggregate exposure.
• A major challenge in estimating aggregate exposure in many product categories is obtaining representative information on exposure factors (Habits and Practices Data, Co-use Data, Chemical Concentration Data and Chemical Occurrence Data), as well as potential correlations between these factors. For some domains, such as household care products, the available data are limited.
• Guidance should be developed to indicate when higher tier aggregate assessments might be a priority. Considerations include relative contributions of different sources, level of conservatism in a screening single source assessment (for example, the case study indicates a higher tier aggregate assessment may produce a lower exposure estimate than the maximum screening exposure predicted for a single uses), and total exposure levels from representative biomonitoring studies.
• Model verification with real-life data (e.g. biomonitoring) on a representative range of chemicals would assist to promote use/acceptance of exposure model predictions.
Wider engagement of industry, the public and regulators into the generation, harmonisation and management of input data related to consumer exposure will foster the advances in aggregate exposure modelling, especially in domains where currently little data are available.
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General default parameters for estimating consumer exposure -
Updated version 2014
In order to assess the potential risks of chemical substances in consumer
products, it is necessary to estimate the consumer exposure during product use.
The computer tool ConsExpo is able to calculate indoor human exposure to
chemical substances in products such as paint, cosmetics or cleaning agents.
The General Fact Sheet describes default values useful for estimating the
exposure to a chemical substance. By using these defaults, the exposure
assessment is performed in a transparent and standardized way. Based on new
available information and developments, RIVM updated the General Fact Sheet
in the current report, which replaces the General Fact Sheet 2006.
The General Fact Sheet contains default values for the room in which the
exposure takes place (for example room size) and for the person that is
exposed, such as body weight and the surface areas of different parts of the
body. In addition, it presents information on the ventilation in houses. Similarly,
information is provided on inhalation rates for adults and children while at rest
and during exercise. New in this version of the fact sheet are data on activity
patterns. The General Fact Sheet explains the underlying data leading to the
defaults and the quality of the default values.
Apart from the General Fact Sheet, there are various product-specific fact
sheets, e.g. for paint, cosmetics, children toys, pest control products, do-ityourself
products, disinfection products and cleaning agents. These fact sheets
contain information, e.g. on the exposure duration and amount of product used.
As personal care products (PCPs) are used in close contact with a person, they are a major source of consumer exposure to chemical substances contained in these products. The estimation of realistic consumer exposure to substances in PCPs is currently hampered by the lack of appropriate data and methods. To estimate aggregate exposure of consumers to substances contained in PCPs, a person-oriented consumer exposure model has been developed (the Probabilistic Aggregate Consumer Exposure Model, PACEM). The model simulates daily exposure in a population based on product use data collected from a survey among the Dutch population. The model is validated by comparing diethyl phthalate (DEP) dose estimates to dose estimates based on biomonitoring data. It was found that the model's estimates compared well with the estimates based on biomonitoring data. This suggests that the person-oriented PACEM model is a practical tool for assessing realistic aggregate exposures to substances in PCPs. In the future, PACEM will be extended with use pattern data on other product groups. This will allow for assessing aggregate exposure to substances in consumer products across different product groups.Journal of Exposure Science and Environmental Epidemiology advance online publication, 29 October 2014; doi:10.1038/jes.2014.68.
In the risk assessment of chemical substances, aggregation of exposure to a substance from different sources via different pathways is not common practice. Focusing the exposure assessment on a substance from a single source can lead to a significant underestimation of the risk. To gain more insight on how to perform an aggregate exposure assessment, we applied a deterministic (tier 1) and a person-oriented probabilistic approach (tier 2) for exposure to the four most common parabens through personal care products in children between 0 and 3 years old. Following a deterministic approach, a worst-case exposure estimate is calculated for methyl-, ethyl-, propyl- and butylparaben. As an illustration for risk assessment, Margins of Exposure (MoE) are calculated. These are 991 and 4966 for methyl- and ethylparaben, and 8 and 10 for propyl- and butylparaben, respectively. In tier 2, more detailed information on product use has been obtained from a small survey on product use of consumers. A probabilistic exposure assessment is performed to estimate the variability and uncertainty of exposure in a population. Results show that the internal exposure for each paraben is below the level determined in tier 1. However, for propyl- and butylparaben, the percentile of the population with an exposure probability above the assumed “safe” MoE of 100, is 13% and 7%, respectively. In conclusion, a tier 1 approach can be performed using simple equations and default point estimates, and serves as a starting point for exposure and risk assessment. If refinement is warranted, the more data demanding person-oriented probabilistic approach should be used. This probabilistic approach results in a more realistic exposure estimate, including the uncertainty, and allows determining the main drivers of exposure. Furthermore, it allows to estimate the percentage of the population for which the exposure is likely to be above a specific value.
The field of toxicology is currently undergoing a global paradigm shift to use of in vitro approaches for assessing the risks of chemicals and drugs in a more mechanistic and high throughput manner than current approaches relying primarily on in vivo testing. However, reliance on in vitro data entails a number of new challenges associated with translating the in vitro results to corresponding in vivo exposures. Physiologically based pharmacokinetic (PBPK) modeling provides an effective framework for conducting quantitative in vitro to in vivo extrapolation (QIVIVE). Their physiological structure facilitates the incorporation of in silico- and in vitro-derived chemical-specific parameters in order to predict in vivo absorption, distribution, metabolism and excretion. In particular, the combination of in silico- and in vitro parameter estimation with PBPK modeling can be used to predict the in vivo exposure conditions that would produce chemical concentrations in the target tissue equivalent to the concentrations at which effects were observed with in vitro assays of tissue/organ toxicity. This review describes the various elements of QIVIVE and highlights key aspects of the process, with an emphasis on extrapolation of in vitro metabolism data to predict in vivo clearance as the key element. Other important elements include characterization of free concentration in the toxicity assay and potential complications associated with intestinal absorption and renal clearance. Examples of successful QIVIVE approaches are described ranging from a simple steady-state approach that is suitable for a high throughput environment to more complicated approaches requiring full PBPK models.
Due to the vast number of possible combinations of chemicals to which individuals are exposed and the resource-intensive nature of cumulative risk assessments, there is a need to determine when cumulative assessments are most required. This paper proposes the use of the maximum cumulative ratio (MCR) as a tool for this evaluation. MCR is the ratio of the cumulative toxicity received by an individual from exposure to multiple chemical stressors to the largest toxicity from a single chemical stressor. The MCR is a quantitative measure of the difference in an individual's toxicity estimated using a chemical-by-chemical approach and using an additive model of toxicity. As such, it provides a conservative estimate of the degree to which individuals' toxicities could be underestimated by not performing a cumulative risk assessment. In an example application, MCR is shown to be applicable to the evaluation of cumulative exposures involving up to 81 compounds and to provide key insights into the cumulative effects posed by exposures to multiple chemicals. In this example, MCR values suggest that individuals exposed to combinations of chemicals with the largest Hazard Indices were dominated by the contributions of one or two compounds.
This paper describes a framework for the risk assessment of combined exposure to multiple chemicals based on and developed subsequent to the World Health Organization/International Programme on Chemical Safety Workshop on Aggregate/Cumulative Risk Assessment (Combined Exposures to Multiple Chemicals) held in 2007. The framework is designed to aid risk assessors in identifying priorities for risk management for a wide range of applications where co-exposures to multiple chemicals are expected. It is based on a hierarchical (phased) approach that involves integrated and iterative consideration of exposure and hazard at all phases, with each tier being more refined (i.e., less cautious and more certain) than the previous one, but more labor and data intensive. It includes reference to predictive and probabilistic methodology in various tiers in addition to tiered consideration of uncertainty. The paper also annexes two case studies that have been developed to test and refine the framework.
This work introduces a specific application of Bayesian nonparametric statistics to the food risk analysis framework. The goal was to determine the cocktails of pesticide residues to which the French population is simultaneously exposed through its current diet in order to study their possible combined effects on health through toxicological experiments. To do this, the joint distribution of exposures to a large number of pesticides, which we called the co-exposure distribution, was assessed from the available consumption data and food contamination analyses. We proposed modelling the co-exposure using a Dirichlet process mixture based on a multivariate Gaussian kernel so as to determine groups of individuals with similar co-exposure patterns. Posterior distributions and the optimal partition were computed through a Gibbs sampler based on stick-breaking priors. The study of the correlation matrix of the sub-population co-exposures will be used to define the cocktails of pesticides to which they are jointly exposed at high doses. To reduce the computational burden due to the high data dimensionality, a random-block sampling approach was used. In addition, we propose to account for the uncertainty of food contamination through the introduction of an additional level of hierarchy in the model. The results of both specifications are described and compared.
Phthalates are metabolized and eliminated in urine within hours after exposure. Several reports suggest that concentrations of phthalate metabolites in a spot urine sample can provide a reliable estimation of exposure to phthalates for up to several months.
We examined inter- and intraperson and inter- and intraday variability in the concentrations of monoethyl phthalate (MEP), the major metabolite of diethyl phthalate, commonly used in personal care products, and mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), a metabolite of di(2-ethylhexyl) phthalate (DEHP), a polyvinyl chloride plasticizer of which diet is the principal exposure source, among eight adults who collected all urine voids (average, 7.6 samples/person/day) for 1 week.
We analyzed the urine samples using online solid-phase extraction coupled to isotope dilution-high-performance liquid chromatography-tandem mass spectrometry.
Regardless of the type of void (spot, first morning, 24-hr collection), for MEP, interperson variability in concentrations accounted for > 75% of the total variance. By contrast, for MEHHP, within-person variability was the main contributor (69-83%) of the total variance. Furthermore, we observed considerable intraday variability in the concentrations of spot samples for MEHHP (51%) and MEP (21%).
MEP and MEHHP urinary concentrations varied considerably during 1 week, but the main contributors to the total variance differed (interday variability, MEHHP; interperson variability, MEP) regardless of the sampling strategy (spot, first morning, 24-hr collection). The nature of the exposure (diet vs. other lifestyle factors) and timing of urine sampling to evaluate exposure to phthalates should be considered. For DEHP and phthalates to which people are mostly exposed through diet, collecting 24-hr voids for only 1 day may not be advantageous compared with multiple spot collections. When collecting multiple spot urine samples, changing the time of collection may provide the most complete approach to assess exposure to diverse phthalates.
Available computer models for estimating the exposure to substances from multiple consumer products are not suited for this task. Consumers are daily exposed to chemical substances from consumer products. The level of this exposure has to be assessed to evaluate the consequences of exposure to a substance for public health. Considering that a substance may be contained in several consumer products (for instance, aromatic substances, flame retardants and softeners), the contribution of these products to the total exposure will have to be added up to determine the aggregate exposure. Aggregate consumer (non-food) exposure is not routinely evaluated in European assessment frameworks. This report examines to what extent available computer models are suited for evaluating aggregate exposure to consumer products. A method for performing aggregate exposure assessment is also described. Dagelijks staat de consument bloot aan chemische stoffen die zijn verwerkt in verschillende (non-food) producten. Om de gevolgen voor de volksgezondheid te kunnen beoordelen moet in de eerste plaats de blootstelling bepaald worden. De optelsom van de totale (geaggregeerde) blootstelling aan een stof uit verschillende consumentenproducten (denk bijvoorbeeld aan geurstoffen, vlamvertragers, weekmakers) moet kunnen worden vastgesteld. Dit rapport kijkt in welke mate bestaande computermodellen geschikt zijn om geaggregeerde blootstelling aan chemische stoffen uit consumentenproducten te bepalen. Op dit moment berekenen de Europese beoordelingskaders deze geaggregeerde consumentenblootstelling (non-food) nog niet routinematig. Als eerste aanzet tot het opvullen van dit hiaat beschrijft dit rapport een methode waarmee een dergelijke geaggregeerde blootstellingsbepaling kan worden uitgevoerd.
The number of personal hygiene products containing triclosan has increased rapidly during the last decade, and triclosan is one of the most common antibacterial compounds used in dentifrices today. However, the extent of triclosan exposure has not yet been well described. The potential risks of generating triclosan-resistant pathogenic microorganisms or of the selection of resistant strains are some areas of concern. The aim of the present study was to (1) obtain information on baseline levels of triclosan in plasma and urine, and (2) study the pharmacokinetic pattern of triclosan after a single-dose intake. Ten healthy volunteers were exposed to a single oral dose of 4 mg triclosan by swallowing an oral mouthwash solution. Triclosan in plasma and urine was followed before and up to 8 d after exposure. Triclosan levels in plasma increased rapidly, with a maximum concentration within 1 to 3 h, and the terminal plasma half-life was 21 h. The major fraction was excreted within the first 24 h. The accumulated urinary excretion varied between the subjects, with 24 to 83% of the oral dose being excreted during the first 4 d after exposure. In conclusion, triclosan appears to be readily absorbed from the gastrointestinal tract and has a rapid turnover in humans. The high lipid solubility of the substance gives rise to questions regarding distribution properties and accumulation. The findings of the present study form a basis for greater understanding of the toxicokinetic properties of triclosan in humans.
Within the framework of the EPHECT project (Emissions, exposure patterns and health effects of consumer products in the EU), irritative and respiratory health effects were assessed in relation to acute and long-term exposure to key and emerging indoor air pollutants emitted during household use of selected consumer products. In this context, inhalation exposure assessment was carried out for six selected 'target' compounds (acrolein, formaldehyde, benzene, naphthalene, d-limonene and α-pinene). This paper presents the methodology and the outcomes from the micro-environmental modelling of the 'target' pollutants following single or multiple use of selected consumer products and the subsequent exposure assessment. The results indicate that emissions from consumer products of benzene and α-pinene were not considered to contribute significantly to the EU indoor background levels, in contrast to some cases of formaldehyde and d-limonene emissions in Eastern Europe (mainly from cleaning products). The group of housekeepers in East Europe appears to experience the highest exposures to acrolein, formaldehyde and benzene, followed by the group of the retired people in North, who experiences the highest exposures to naphthalene and α-pinene. High exposure may be attributed to the scenarios developed within this project, which follow a 'most-representative worst-case scenario' strategy for exposure and health risk assessment. Despite the above limitations, this is the first comprehensive study that provides exposure estimates for 8 population groups across Europe exposed to 6 priority pollutants, as a result of the use of 15 consumer product classes in households, while accounting for regional differences in uses, use scenarios and ventilation conditions of each region.
Crown Copyright © 2015. Published by Elsevier B.V. All rights reserved.
2-Phenoxyethanol (PhE) has been shown to induce hepatotoxicity, renal toxicity, and hemolysis at dosages > 400 mg/kg/day in subchronic and chronic studies in multiple species. To reduce uncertainty associated with interspecies extrapolations and to evaluate the margin of exposure (MOE) for use of PhE in cosmetics and baby products, a physiologically-based pharmacokinetic (PBPK) model of PhE and its metabolite 2-phenoxyacetic acid (PhAA) was developed. The PBPK model incorporated key kinetic processes describing the absorption, distribution, metabolism and excretion of PhE and PhAA following oral and dermal exposures. Simulations of repeat dose rat studies facilitated the selection of systemic AUC as the appropriate dose metric for evaluating internal exposures to PhE and PhAA in rats and humans. Use of the PBPK model resulted in refinement of the total default UF for extrapolation of the animal data to humans from 100 to 25. Based on very conservative assumptions for product composition and aggregate product use, model-predicted exposures to PhE and PhAA resulting from adult and infant exposures to cosmetic products are significantly below the internal dose of PhE observed at the NOAEL dose in rats. Calculated MOEs for all exposure scenarios were above the PBPK-refined UF of 25.
Copyright © 2015. Published by Elsevier Inc.
Consumer products are frequently and regularly used in the domestic environment. Realistic estimates for product use are required for exposure modelling and health risk assessment. This paper provides significant data that can be used as input for such modelling studies. A European survey was conducted, within the framework of the DG Sanco-funded EPHECT project, on the household use of 15 consumer products. These products are all-purpose cleaners, kitchen cleaners, floor cleaners, glass and window cleaners, bathroom cleaners, furniture and floor polish products, combustible air fresheners, spray air fresheners, electric air fresheners, passive air fresheners, coating products for leather and textiles, hair styling products, spray deodorants and perfumes. The analysis of the results from the household survey (1st phase) focused on identifying consumer behaviour patterns (selection criteria, frequency of use, quantities, period of use and ventilation conditions during product use). This can provide valuable input to modelling studies, as this information is not reported in the open literature. The above results were further analysed (2nd phase), to provide the basis for the development of 'most representative worst-case scenarios' regarding the use of the 15 products by home-based population groups (housekeepers and retired people), in four geographical regions in Europe. These scenarios will be used for the exposure and health risk assessment within the EPHECT project. To the best of our knowledge, it is the first time that daily worst-case scenarios are presented in the scientific published literature concerning the use of a wide range of 15 consumer products across Europe.
Crown Copyright © 2015. Published by Elsevier B.V. All rights reserved.
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.
Copyright © 2015 Elsevier Ltd. All rights reserved.
This paper provides a model to assess dietary exposure to flavouring substances intentionally added to food. The purpose is to describe the approaches currently available and their scientific basis. The proposed exposure model for flavouring substances envisages three different levels of refinement: basic, intermediate and refined. At the two first levels, the model may be applied to all 2543 substances actually in use in Europe, while the refined level has been applied to 41 target flavouring substances selected within the FACET project. The refined level entails the use of the probability of addition of the flavouring substance added to the food and of correction factors related to losses owing to the processing of a food.
Glycol ethers are a class of semi-volatile substances used as solvents in a variety of consumer products like cleaning agents, paints, cosmetics as well as chemical intermediates. We determined 11 metabolites of ethylene and propylene glycol ethers in 44 urine samples of German residents (background level study) and in urine samples of individuals after exposure to glycol ethers during cleaning activities (exposure study). In the study on the background exposure, methoxyacetic acid and phenoxyacetic acid (PhAA) could be detected in each urine sample with median (95th percentile) values of 0.11mgL(-1) (0.30mgL(-1)) and 0.80mgL(-1) (23.6mgL(-1)), respectively. The other metabolites were found in a limited number of samples or in none. In the exposure study, 5-8 rooms were cleaned with a cleaner containing ethylene glycol monobutyl ether (EGBE), propylene glycol monobutyl ether (PGBE), or ethylene glycol monopropyl ether (EGPE). During cleaning the mean levels in the indoor air were 7.5mgm(-3) (EGBE), 3.0mgm(-3) (PGBE), and 3.3mgm(-3) (EGPE), respectively. The related metabolite levels analysed in the urine of the residents of the rooms at the day of cleaning were 2.4mgL(-1) for butoxyacetic acid, 0.06mgL(-1) for 2-butoxypropionic acid, and 2.3mgL(-1) for n-propoxyacetic acid. Overall, our study indicates that the exposure of the population to glycol ethers is generally low, with the exception of PhAA. Moreover, the results of the cleaning scenarios demonstrate that the use of indoor cleaning agents containing glycol ethers can lead to a detectable internal exposure of residents.
Complete information regarding the use of personal care products (PCPs) by consumers is scarce, but such information is crucial for realistic consumer exposure assessment. To fill this gap, we created a database with person-oriented information regarding usage patterns and circumstances of use for 32 different PCPs. Out of 2700 potential participants in the Netherlands, 516 men and women completed a digital questionnaire. The prevalence of use varied by gender, age, level of education and skin type. We observed a high frequency of use for some products (e.g. lip care products), while toothpaste, deodorant and day cream were generally used once or twice a day. The frequency of use for other PCPs varied over a wide range. The amounts of use varied largely between and within different product groups. Body lotion, sunscreen and after sun lotion were often applied on adjacent body parts. The majority of PCPs were applied in the morning, but some products, such as night cream and after sun, were predominantly applied in the evening or night. As expected, the participants used several PCPs simultaneously. The database yields important personalized exposure factors which can be used in aggregate consumer exposure assessment for substances that are components of PCPs.
Biomarker concentrations in spot samples of blood and urine are implicitly interpreted as direct surrogates for long-term exposure magnitude in a variety of contexts including (1) epidemiological studies of potential health outcomes associated with general population chemical exposure, and (2) cross-sectional population biomonitoring studies. However, numerous factors in addition to exposure magnitude influence biomarker concentrations in spot samples, including temporal variation in spot samples because of elimination kinetics. The influence of half-life of elimination relative to exposure interval is examined here using simple first-order pharmacokinetic simulations of urinary concentrations in spot samples collected at random times relative to exposure events. Repeated exposures were modeled for each individual in the simulation with exposure amounts drawn from lognormal distributions with varying geometric standard deviations. Relative variation in predicted spot sample concentrations was greater than the variation in underlying dose distributions when the half-life of elimination was shorter than the interval between exposures, with the degree of relative variation increasing as the ratio of half-life to exposure interval decreased. Results of the modeling agreed well with data from a serial urine collection data set from the Centers for Disease Control. Data from previous studies examining intra-class correlation coefficients for a range of chemicals relying upon repeated sampling support the importance of considering the half-life relative to exposure frequency in design and interpretation of studies using spot samples for exposure classification and exposure estimation. The modeling and data sets presented here provide tools that can assist in interpretation of variability in cross-sectional biomonitoring studies and in design of studies utilizing biomonitoring data as markers for exposure.
A study of the relationship between outside air ventilation rate and concentrations of volatile organic compounds (VOCs) generated indoors was conducted in a call center office building. The building, with two floors and a total floor area of 4600 m2, is located in the San Francisco Bay Area, CA. Ventilation rates were manipulated with the building's four air handling units (AHUs). VOC and CO2 concentrations in the AHU returns were measured on 7 days during a 13-week period. VOC emission factors were determined for individual zones on days when they were operating at near steady-state conditions. The emission factor data were subjected to principal component (PC) analysis to identify groups of co-varying compounds. Potential sources of the PC vectors were ascribed based on information from the literature. The per occupant CO2 generation rates were 0.0068–0.0092 l s−1. The per occupant isoprene generation rates of 0.2–0.3 mg h−1 were consistent with the value predicted by mass balance from breath concentration and exhalation rate. The relationships between indoor minus outdoor VOC concentrations and ventilation rate were qualitatively examined for eight VOCs. Of these, acetaldehyde and hexanal, which likely were associated with material sources, and decamethylcyclopentasiloxane, associated with personal care products, exhibited general trends of higher concentrations at lower ventilation rates. For other compounds, a clear inverse relationship between VOC concentrations and ventilation was not observed. The net concentration of 2,2,4-trimethyl-1,3-pentanediol monoisobutyrate isomers, examples of low-volatility compounds, changed very little with ventilation likely due to sorption and re-emission effects. These results illustrate that the efficacy of ventilation for controlling VOC concentrations can vary considerably depending upon the operation of the building, the pollutant sources and the physical and chemical processes affecting the pollutants. Thus, source control measures, in addition to adequate ventilation, are required to limit concentrations of VOCs in office buildings.
Access to reliable exposure data is essential for the evaluation of the toxicological safety of ingredients in cosmetic products. This study complements the data set obtained previously (Part 1) and published in 2007 by the European cosmetic industry acting within COLIPA. It provides, in distribution form, exposure data on daily quantities of five cosmetic product types: hair styling, hand cream, liquid foundation, mouthwash and shower gel. In total 80,000 households and 14,413 individual consumers in five European countries provided information using their own products. The raw data were analysed using Monte Carlo simulation and a European Statistical Population Model of exposure was constructed. A significant finding was an inverse correlation between the frequency of product use and the quantity used per application recorded for mouthwash and shower gel. The combined results of Part 1 (7 product types) and Part 2 (5 products) reported here, bring up to date and largely confirm the current exposure parameters concerning some 95% of the estimated daily exposure to cosmetics use in the EU. The design of this study, with its relation to demographic and individual diversity, could serve as a model for studies of populations' exposure to other consumer products.
The introduction of in vitro methodologies in the toxicological risk assessment process requires a number of prerequisites regarding both the toxicodynamics and the biokinetics of the compounds under study. In vitro systems will need to be relevant for measuring those structural and physiological changes that are good indicators for adverse effects. Furthermore, the dose metric found to have an effect in the in vitro system should be relevant. One element in defining the appropriate dose metric is related to the kinetic behavior of the compound in the in vitro system: binding to proteins, binding to plastic, evaporation, and the interaction between the culture medium and the cells. Ways to measure and model "in vitro biokinetics" are described. Second, the appropriate dose metric in vitro, e.g., the effective concentration, will need to be extrapolated to relevant in vivo exposure scenarios. The application of physiologically based biokinetic modelling is essential in such extrapolations. The parameters needed to build these models often can be estimated based on nonanimal data, namely chemical properties (QSARs) and in vitro experiments.
Exposure to compounds in consumer products can be assessed using the computer program ConsExpo (Consumer Exposure). Given the huge number of consumer products, it is not possible to calculate the exposure for each separate product, so a limited number of groups containing similar products are defined. The information for each group of products is described in a fact sheet. Paint, cosmetics, children's toys and pest control products are examples of fact sheets which have been published already. This fact sheet covers the use of cleaning products by consumers. In the fact sheet 36 product categories are described including laundry detergents, dishwashing products, abrasives and toilet cleaners. To assess exposure of compounds in the cleaning products default values for all 36 product categories have been determined. Een snelle, transparante en gestandaardiseerde blootstellingsschatting van reinigingsmiddelen is dankzij een nieuwe factsheet voor het computerprogramma ConsExpo nu mogelijk. ConsExpo 4.0 is een computerprogramma, dat gebruikt kan worden om de blootstelling van mensen aan stoffen in consumentenproducten uit te rekenen. Hierbij wordt rekening gehouden met verschillende blootstellingsroutes (dus via de huid, via inhalatie en via orale opname). Bij het ConsExpo programma hoort ook een database, waarin standaardwaarden voor vele product typen en voor een groot aantal blootstellingsscenarios worden aangeboden. De beschrijving van deze achtergrondinformatie bij deze standaardwaarden wordt gerapporteerd in zogenoemde 'factsheets'. In dit rapport, factsheet reinigingsmiddelen, is de meest recente informatie bijeengebracht om de blootstelling aan stoffen uit reinigingsmiddelen te berekenen. De verschillende typen reinigingsmiddelen zijn verdeeld in 36 categorien, bijvoorbeeld wasmiddelen, afwasmiddelen, schuurmiddelen en toiletreinigers. Voor iedere categorie wordt de samenstelling en gebruik van producten uit die categorie beschreven. Daarnaast wordt aangegeven welk model of modellen van ConsExpo het meest geschikt is om de blootstelling uit te rekenen en worden voor alle gegevens die nodig zijn voor de berekening standaardwaarden ingevuld. Naast deze factsheet reinigingsmiddelen zijn er ook factsheets voor ongediertebestrijdingsmiddelen, verf, cosmetica en desinfectantia.
The need to understand and estimate quantitatively the aggregate exposure to ingredients used broadly in a variety of product types continues to grow. Currently aggregate exposure is most commonly estimated by using a very simplistic approach of adding or summing the exposures from all the individual product types in which the chemical is used. However, the more broadly the ingredient is used in related consumer products, the more likely this summation will result in an unrealistic estimate of exposure because individuals in the population vary in their patterns of product use including co-use and non-use. Furthermore the ingredient may not be used in all products of a given type. An approach is described for refining this aggregate exposure using data on (1) co-use and non-use patterns of product use, (2) extent of products in which the ingredient is used and (3) dermal penetration and metabolism. This approach and the relative refinement in the aggregate exposure from incorporating these data is illustrated using methyl, n-propyl, n-butyl and ethyl parabens, the most widely used preservative system in personal care and cosmetic products. When these refining factors were used, the aggregate exposure compared to the simple addition approach was reduced by 51%, 58%, 90% and 92% for methyl, n-propyl, n-butyl and ethyl parabens, respectively. Since biomonitoring integrates all sources and routes of exposure, the estimates using this approach were compared to available paraben biomonitoring data. Comparison to the 95th percentile of these data showed that these refined estimates were still conservative by factors of 2-92. All of our refined estimates of aggregate exposure are less than the ADI of 10mg/kg/day for parabens.
Ethylene glycol ethers (EGEs) are primary alcohols commonly used as solvents in numerous household and industrial products. Exposure to EGEs has been correlated with delayed encephalopathy, metabolic acidosis, sub-fertility and spermatotoxicity in humans. In addition, they also cause teratogenesis, carcinogenesis, hemolysis, etc., in various animal models. Metabolism EGEs parallels ethanol metabolism, i.e., EGEs are first converted to 2-alkoxy acetaldehydes (EGE aldehydes) by alcohol dehydrogenases, and then to alkoxyacetic acids by aldehyde dehydrogenases (ALDHs). The acid metabolite of EGEs is considered responsible for toxicities associated with EGEs. The role of human ALDHs in EGE metabolism is not clear; accordingly, we have investigated the ability of five different human ALDHs (ALDH1A1, ALDH2, ALDH3A1, ALDH5A1 and ALDH9A1) to catalyze the oxidation of various EGE aldehydes. The EGE aldehydes used in this study were synthesized via Swern oxidation. All of the human ALDHs were purified from human cDNA clones over-expressing these enzymes in E. coli. The ALDHs tested, so far, differentially catalyze the oxidation of EGE aldehydes to their corresponding acids (K(m) values range from approximately 10 microM to approximately 20.0mM). As judged by V(max)/K(m) ratios, short-chain alkyl-group containing EGE aldehydes are oxidized to their acids more efficiently by ALDH2, whereas aryl- and long-chain alkyl-group containing EGE aldehydes are oxidized to their acid more efficiently by ALDH3A1. Given the product of ALDH-catalyzed reaction is toxic, this process should be considered as a bio-activation (toxification) process.
Both homeostatic and rhythmic variables are empirically and theoretically important controls of behavior. Yet, drinking behavior has been studied largely from one point of view or the other. The present study examined both homeostatic and rhythmic variables and found evidence for an important interaction of these two types of control of drinking behavior. The drinking rhythm of rats on a light-dark cycle was established. Water intake after cellular- or extracellular-related challenges was then measured both at a time of a peak and at a time of a trough of the drinking rhythm. The results indicate that rats drink more water after challenges in their early active phase than in their early inactive phase. The results demonstrate that rhythmic variables modulate the homeostatic controls of drinking behavior. The importance of the interaction of homeostatic and rhythmic variables in models of integrative control of behavior is discussed.
triclosan is widely used in many products that contact the skin of consumers. This study compares in vivo and in vitro skin absorption of triclosan and determines the potential of skin to metobolize it prior to entering the blood stream. After in vivo topical application of a 64.5mM alcoholic solution of [(3)H]triclosan to rat skin, 12% radioactivity was recovered in the faeces, 8% in the carcass 1% in the urine, 30% in the stratum corneum and 26% was rinsed from the skin surface at 24 hours after application. Free triclosan and the glucuronide and sulfate conjugates of triclosan were found in urine and faeces. triclosan penetrated rat skin more rapidly and extensively than human skin in vitro. 23% of the dose had penetrated completely through rat skin into the receptor fluid by 24 hours, whereas penetration through human skin was only 6.3% of the dose. Chromatographic analysis of the receptor solutions showed that triclosan was metabolized to the glucuronide, and to a lesser extent to the sulfate, during passage through the skin. triclosan glucuronide appeared rapidly in the receptor fluid whereas triclosan sulfate remained in the skin. Although the major site of metabolism was the liver, conjugation of triclosan in skin was also demonstrated in vitro and in vivo, particularly to the glucuronide conjugate which was more readily removed from the skin. The in vitro system provides a reasonable estimate of dermal absorption in vivo for the rat. Therefore by extrapolation of the comparative in vitro data for human and rat skin it is reasonable to deduce that dermal absorption in human of triclosan applied at the same dose is about one-third of that in the rat in vivo.
To determine clinically the buccal absorption and plaque retention of triclosan from a mouthrinse containing 0.03% triclosan.
15 ml of the triclosan oral rinse (N=9) or placebo mouthrinse (N=12) was used twice daily for 21 days in humans. Blood, dental plaque and the expectorated oral rinse were collected prior to, during the treatment period at given intervals, and 8 days after the treatment. Dental plaque and blood samples were collected 1 hr and 4 hr after the morning rinse, respectively. The oral retention of triclosan was calculated by subtracting the amount of triclosan recovered in the expectorate from the triclosan dose applied (4.50 mg) in the mouthrinse. Plasma samples were analyzed for free triclosan (the parent molecule) and its glucuronide and sulfate conjugates, whereas dental plaque was analyzed only for total triclosan.
No significant treatment-related adverse effects were observed during the clinical phase of the study. The average daily oral retention of triclosan was calculated to be 0.660 mg, which is 7.33% of the triclosan dose applied (2 x 4.50 mg). Plaque contained an average 20.5-46.4 microg of triclosan per g of plaque collected. At various sampling times, mean plasma concentrations were: no detectable triclosan, 63.8-86.3 microg/ml of triclosan glucuronide and 8.23-18.0 ng/ml of triclosan sulfate. The mean total triclosan plasma concentration ranged from 74.5 to 94.2 microg/ml with plateau concentrations reached after 2 days of dosing. Eight days after the last treatment the triclosan plasma concentration returned to baseline levels (< 2 ng/ml).
In preterm newborn infants, topical iodine-containing antiseptics disturb thyroid hormone regulation while alcohol-based disinfectants may cause local burns. We therefore investigated the use of an aqueous solution containing 0.1% octenidine and 2% 2-phenoxyethanol for skin disinfection during the first seven days of life in premature newborns with a gestational age <27 weeks who were consecutively admitted to our level III neonatal intensive care unit between November 1, 2000 and December 31, 2001 (N=24). In boys. (N=13) the renal excretion of absorbed 2-phenoxyethanol and its metabolite 2-phenoxyacetic acid was quantitated by high-pressure liquid chromatography. In the most immature newborn (gestational age 23 6/7 weeks), a transient erythematous reaction was observed following application of the octenidine/phenoxyethanol solution prior to umbilical vessel catheterization. No other local reactions were observed. The urinary concentration of 2-phenoxyethanol was <2 ppm in all samples, while urinary 2-phenoxyacetic acid concentrations reached 5-95 ppm (median 24 ppm). One infant had a culture-proven septicaemia (Bacillus species) during the first seven days of life. We conclude that, in contrast to alcohol-based antiseptics, an aqueous solution of 0.1% octenidine and 2-phenoxyethanol does not cause major skin damage in premature newborn infants <27 weeks' gestation. 2-Phenoxyethanol is readily absorbed by the newborn's skin but apparently undergoes extensive oxidative metabolization to 2-phenoxyacetic acid.
Accurate exposure information for cosmetic products and ingredients is needed in order to conduct safety assessments. Essential information includes both the amount of cosmetic product applied, and the frequency of use. To obtain current data, a study to assess consumer use practices was undertaken. The study included three widely used cosmetic product types: lipstick, body lotion, and face cream. Three hundred and sixty women, ages 19-65 years, who regularly use the products of interest, were recruited at ten different geographical locations within the US. The number of recruits was chosen to ensure a minimum of 300 completes per product type. Subjects were provided with prototype test products, and kept diaries and recorded detailed daily usage information over a two week period. Products were weighed at the start and completion of the study in order to determine the total amount of product used. Statistical analysis of the data was conducted to derive summary distribution of use patterns. The mean and median usage per application, respectively, for the three products was: face cream, 1.22 g and 0.84 g; lipstick, 10 mg and 5 mg; and body lotion, 4.42 g and 3.45 g. The mean and median usage per day for the three products was: face cream, 2.05 g and 1.53 g; lipstick, 24 mg and 13 mg; and body lotion, 8.70 g and 7.63 g. The mean number of applications per day for face cream and lipstick was 1.77 and 2.35, respectively. For body lotion, the mean number of applications per day was dependent on body area, and was 2.12, 1.52, 1.11, 0.95, 0.43, 0.26, and 0.40 for hands, arms, legs, feet, neck and throat, back, and other body areas, respectively. The effect of product preference on use practices was also investigated. This study provides current cosmetic exposure information for commonly used products which will be useful for risk assessment purposes.
Computer modeling of aggregate exposure provides the capability to estimate the range of doses that can occur from product use and to understand the relative importance of different routes of exposure. This paper presents an assessment of aggregate occupational exposure to two glycol ethers used as solvents in floor maintenance products for industrial and institutional facilities, using a simulation tool named PROMISE. Three commercial floor-care products were assumed to be applied in sequence--a floor stripper, then a floor cleaner, and lastly a protective coating. The glycol ethers modeled were ethylene glycol butyl ether (EGBE) in the floor stripper and in the floor cleaner, and dipropylene glycol methyl ether (DPGME) in the coating. Modeling uncertainty was assessed through a comparison of the PROMISE inhalation exposure estimates with those from an independent model (MCCEM), and parameter uncertainty was investigated using PROMISE software's Monte Carlo simulation capabilities. Modeling results indicated that inhalation is the dominant exposure route. The predicted average air concentration and inhalation dose from PROMISE agreed with the second model (MCCEM) within 10%. Monte Carlo simulation indicated that the upper end of the aggregate-dose distribution for the scenario was more than 50% higher than the value of the point estimate. The modeled 8-h TWA concentrations for EGBE and DPGME were lower than the corresponding permissible exposure limits American Conference of Governmental Industrial Hygienists (ACGIH) Threshold Limit Values (TLV) by at least a factor of 20, indicating that under the assumed conditions workplace exposures to glycol ethers are below levels of concern.
Reliable exposure information for cosmetic and other personal care products and ingredients is needed in order to conduct safety assessments. Essential information includes both the amount of product applied, and the frequency of use. To obtain current data, studies to assess consumer use practices were undertaken. Six widely used personal care product types were included in the studies. Five of the products were cosmetics (spray perfume, hairspray, liquid foundation, shampoo, body wash) and one product was a cosmetic/over-the-counter drug product (solid antiperspirant). Three hundred and sixty women, ages 19-65 years, who regularly use the products of interest, were recruited at 10 different geographical locations within the US. The number of recruits was chosen to ensure a minimum of three hundred completed responses per product type. Subjects were provided with a new container of the brand of product they normally use and kept diaries and recorded detailed daily usage information over a two week period. Products were weighed at the start and completion of the study in order to determine the total amount of product used. Statistical analyses of the data were conducted to derive summary distributions of use patterns. The geometric mean and median usage per application, respectively, for the six product types were: spray perfume, 0.33 g and 0.23 g; hairspray, 2.58 g and 1.83 g (aerosol); 3.64 g and 2.66 g (pump); liquid foundation, 0.54 g and 0.36 g; shampoo, 11.76 g and 9.56 g; body wash, 11.3g and 9.5 g; and solid antiperspirant, 0.61 g and 0.45 g. The mean and median usage per day for the six product types were: spray perfume, 0.53 g and 0.34 g; hairspray, 3.57 g and 2.71 g (aerosol); 5.18 g and 3.74 g (pump); liquid foundation, 0.67 g and 0.45 g; shampoo, 12.80 g and 10.75 g; body wash, 14.5 g and 12.9 g; and solid antiperspirant, 0.79 g and 0.59 g. The mean number of applications per day for spray perfume, hairspray, liquid foundation, shampoo, body wash, and solid antiperspirant was 1.67, 1.49 (aerosol) and 1.51 (pump), 1.24, 1.11, 1.37, and 1.3, respectively. This study provides current exposure information for commonly used products which will be useful for risk assessment purposes.
Access to reliable exposure data is essential to evaluate the toxicological safety of ingredients in cosmetic products. This study was carried out by European cosmetic manufacturers acting within the trade association Colipa, with the aim to construct a probabilistic European population model of exposure. The study updates, in distribution form, the current exposure data on daily quantities of six cosmetic products. Data were collected using a combination of market information databases and a controlled product use study. In total 44,100 households and 18,057 individual consumers in five European countries provided data using their own products. All product use occasions were recorded, including those outside of home. The raw data were analysed using Monte Carlo simulation and a European Statistical Population Model of exposure was constructed. A significant finding was an inverse correlation between frequency of product use and quantity used per application for body lotion, facial moisturiser, toothpaste and shampoo. Thus it is not appropriate to calculate daily exposure to these products by multiplying the maximum frequency value by the maximum quantity per event value. The results largely confirm the exposure parameters currently used by the cosmetic industry. Design of this study could serve as a model for future assessments of population exposure to chemicals in products other than cosmetics.
An international workshop was held in 2006 to evaluate experimental techniques for hazard identification and hazard characterization of sensitizing agents in terms of their ability to produce data, including dose-response information, to inform risk assessment. Human testing to identify skin sensitizers is discouraged for ethical reasons. Animal-free alternatives, such as quantitative structure-activity relationships and in vitro testing approaches, have not been sufficiently developed for such application. Guinea pig tests do not generally include dose-response assessment and are therefore not designed for the assessment of potency, defined as the relative ability of a chemical to induce sensitization in a previously naive individual. In contrast, the mouse local lymph node assay does include dose-response assessment and is appropriate for this purpose. Epidemiological evidence can be used only under certain circumstances for the evaluation of the sensitizing potency of chemicals, as it reflects degree of exposure as well as intrinsic potency. Nevertheless, human diagnostic patch test data and quantitative elicitation data have provided very important information in reducing allergic contact dermatitis risk and sensitization in the general population. It is therefore recommended that clinical data, particularly dose-response data derived from sensitized patients, be included in risk assessment.
Reliable exposure information for cosmetic and other personal care products and ingredients is needed in order to conduct safety assessments. Essential information includes both the amount of product applied, and the frequency of use. To obtain current data, a study to assess consumer use practices was undertaken. Three widely used types of cosmetic products - facial cleanser, hair conditioner, and eye shadow - were included in the study. Three hundred and sixty women, ages 18-69 years, who regularly use the products of interest, were recruited nationwide within the US. Subjects were provided with a new container of the brand of product they normally use and kept diaries and recorded detailed daily usage information over a two week period. Products were weighed at the start and completion of the study in order to determine the total amount of product used. Statistical analyses of the data were conducted to derive summary distributions of use patterns. The mean and median usage per application, respectively, for the three product types were: facial cleanser, 2.57 g and 2.11 g; hair conditioner, 13.13 g and 10.21 g; and eye shadow, 0.03 g and 0.009 g. The mean and median usage per day for the three product types was: facial cleanser, 4.06 g and 3.25 g; hair conditioner, 13.77 g and 10.62 g; and eye shadow, 0.04 g and 0.010 g. The mean number of applications per day for facial cleanser, hair conditioner, and eye shadow was 1.6, 1.1, and 1.2, respectively. This study provides an estimate of current exposure information for commonly used products which will be useful for risk assessment purposes.
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