Assessing the safety of co-exposure to food packaging migrants in food and water using the maximum cumulative ratio and an established decision tree.

Food contact materials can release low levels of multiple chemicals (migrants) into foods and beverages, to which individuals can be exposed through food consumption. This paper investigates the potential for non-carcinogenic effects from exposure to multiple migrants using the Cefic Mixtures Ad hoc Team (MIAT) decision tree. The purpose of the assessment is to demonstrate how the decision tree can be applied to concurrent exposures to multiple migrants using either hazard or structural data on the specific components, i.e. based on the acceptable daily intake (ADI) or the threshold of toxicological concern. The tree was used to assess risks from co-exposure to migrants reported in a study on non-intentionally added substances (NIAS) eluting from food contact-grade plastic and two studies of water bottles: one on organic compounds and the other on ionic forms of various elements. The MIAT decision tree assigns co-exposures to different risk management groups (I, II, IIIA and IIIB) based on the hazard index, and the maximum cumulative ratio (MCR). The predicted co-exposures for all examples fell into Group II (low toxicological concern) and had MCR values of 1.3 and 2.4 (indicating that one or two components drove the majority of the mixture's toxicity). MCR values from the study of inorganic ions (126 mixtures) ranged from 1.1 to 3.8 for glass and from 1.1 to 5.0 for plastic containers. The MCR values indicated that a single compound drove toxicity in 58% of the mixtures. MCR values also declined with increases in the hazard index for the screening assessments of exposure (suggesting fewer substances contributed as risk potential increased). Overall, it can be concluded that the data on co-exposure to migrants evaluated in these case studies are of low toxicological concern and the safety assessment approach described in this paper was shown to be a helpful screening tool.

Applying the maximum cumulative ratio methodology to biomonitoring data on dioxin-like compounds in the general public and two occupationally exposed populations.

Maximum cumulative ratio (MCR) is a person's cumulative exposure to multiple chemicals divided by the maximum chemical-specific exposure where exposure is expressed on a toxicologically equivalent basis. It is a tool for assessing the need for performing cumulative exposure assessments. In this paper, MCR values were calculated for the three groups of individuals with biomonitoring data of 26 dioxin-like compounds (DLCs) based on the World Health Organization toxic equivalent factors (TEFs). Although the two occupational groups have higher total toxicity equivalence (TEQ) levels than the NHANES group, average MCR values of the three groups are similar (3.5, 3.6, and 3.2). These MCR values are higher than those seen in our earlier studies, supporting the practice of performing cumulative assessments for DLCs. The MCR values also indicate that only 2-5 of the 26 chemicals make significant contributions to total TEQ values. Interestingly, MCR is negatively correlated with total TEQ (in all the three groups) and age (in the NHANES group). Additionally, MCR is lower in workers where occupational exposures are larger than background exposures. Although overall exposure is the first factor to consider in any mixtures assessment, this paper confirms the usefulness of MCR as a tool for analyzing the pattern of chemical-specific contributions to the total exposure levels of mixtures based on biomonitoring data when TEFs or similar approaches are available.

Assessing the relevance of in vitro studies in nanotoxicology by examining correlations between in vitro and in vivo data.

There is an urgent need for in vitro screening assays to evaluate nanoparticle (NP) toxicity. However, the relevance of in vitro assays is still disputable. We administered doses of TiO(2) NPs of different sizes to alveolar epithelial cells in vitro and the same NPs by intratracheal instillation in rats in vivo to examine the correlation between in vitro and in vivo responses. The correlations were based on toxicity rankings of NPs after adopting NP surface area as dose metric, and response per unit surface area as response metric. Sizes of the anatase TiO(2) NPs ranged from 3 to 100 nm. A cell-free assay for measuring reactive oxygen species (ROS) was used, and lactate dehydrogenase (LDH) release, and protein oxidation induction were the in vitro cellular assays using a rat lung Type I epithelial cell line (R3/1) following 24 h incubation. The in vivo endpoint was number of PMNs in bronchoalveolar lavage fluid (BALF) after exposure of rats to the NPs via intratracheal instillation. Slope analyses of the dose response curves shows that the in vivo and in vitro responses were well correlated. We conclude that using the approach of steepest slope analysis offers a superior method to correlate in vitro with in vivo results of NP toxicity and for ranking their toxic potency.

Maximum cumulative ratio (MCR) as a tool for assessing the value of performing a cumulative risk assessment.

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.

Validation of an LDH assay for assessing nanoparticle toxicity.

Studies showed that certain cytotoxicity assays were not suitable for assessing nanoparticle (NP) toxicity. We evaluated a lactate dehydrogenase (LDH) assay for assessing copper (Cu-40, 40nm), silver (Ag-35, 35nm; Ag-40, 40nm), and titanium dioxide (TiO(2)-25, 25nm) NPs by examining their potential to inactivate LDH and interference with ß-nicotinamide adenine dinucleotide (NADH), a substrate for the assay. We also performed a dissolution assay for some of the NPs. We found that the copper NPs, because of their high dissolution rate, could interfere with the LDH assay by inactivating LDH. Ag-35 could also inactivate LDH probably because of the carbon matrix used to cage the particles during synthesis. TiO(2)-25 NPs were found to adsorb LDH molecules. In conclusion, NP interference with the LDH assay depends on the type of NPs and the suitability of the assay for assessing NP toxicity should be examined case by case.

Determining the maximum cumulative ratios for mixtures observed in ground water wells used as drinking water supplies in the United States.

The maximum cumulative ratio (MCR) developed in previous work is a tool to evaluate the need to perform cumulative risk assessments. MCR is the ratio of the cumulative exposures to multiple chemicals to the maximum exposure from one of the chemicals when exposures are described using a common metric. This tool is used to evaluate mixtures of chemicals measured in samples of untreated ground water as source for drinking water systems in the United States. The mixtures of chemicals in this dataset differ from those examined in our previous work both in terms of the predicted toxicity and compounds measured. Despite these differences, MCR values in this study follow patterns similar to those seen earlier. MCR values for the mixtures have a mean (range) of 2.2 (1.03-5.4) that is much smaller than the mean (range) of 16 (5-34) in the mixtures in previous study. The MCR values of the mixtures decline as Hazard Index (HI) values increase. MCR values for mixtures with larger HI values are not affected by possible contributions from chemicals that may occur at levels below the detection limits. This work provides a second example of use of the MCR tool in the evaluation of mixtures that occur in the environment.

Concept of assessing nanoparticle hazards considering nanoparticle dosemetric and chemical/biological response metrics.

Engineered nanoparticles (NP) are being developed and incorporated in a number of commercial products, raising the potential of human exposure during manufacture, use, and disposal. Although data concerning the potential toxicity of some NP have been reported, validated simple assays are lacking for predicting their in vivo toxicity. The aim of this study was to evaluate new response metrics based on chemical and biological activity of NP for screening assays that can be used to predict NP toxicity in vivo. Two cell-free and two cell-based assays were evaluated for their power in predicting in vivo toxicity of eight distinct particle types with widely differing physicochemical characteristics. The cell-free systems comprised fluorescence- and electron spin resonance-based assays of oxidant activity. The cell-based systems also used electron spin resonance (ESR) as well as luciferase reporter activity to rank the different particle types in comparison to benchmark particles of low and high activity. In vivo experiments evaluated acute pulmonary inflammatory responses in rats. Endpoints in all assays were related to oxidative stress and responses were expressed per unit NP surface area to compare the results of different assays. Results indicated that NP are capable of producing reactive species, which in biological systems lead to oxidative stress. Copper NP had the greatest activity in all assays, while TiO(2) and gold NP generally were the least reactive. Differences in the ranking of NP activity among the assays were found when comparisons were based on measured responses. However, expressing the chemical (cell-free) and biological (cells; in vivo) activity per unit particle surface area showed that all in vitro assays correlated significantly with in vivo results, with the cellular assays correlating the best. Data from this study indicate that it is possible to predict acute in vivo inflammatory potential of NP with cell-free and cellular assays by using NP surface area-based dose and response metrics, but that a cellular component is required to achieve a higher degree of predictive power.

A review of traffic-related air pollution exposure assessment studies in the developing world.

Exposure assessment studies in the developing world are important. Although recent years have seen an increasing number of traffic-related pollution exposure studies, exposure assessment data on this topic are still limited. Differences among measuring methods and a lack of strict quality control in carrying out exposure assessment make it difficult to generalize and compare findings between studies. In this article, exposure assessment studies carried out in the developing world on several traffic-related air pollutants are reviewed. These pollutants include particulate matter (PM), carbon monoxide (CO), nitrogen dioxide (NO(2)), volatile organic compounds (VOCs), and polycyclic aromatic hydrocarbons (PAHs). In addition, it discusses advantages and disadvantages of various monitoring methods (ambient fixed-site monitoring, microenvironment monitoring, and personal exposure assessment using portable samplers) for these pollutants in exposure assessment studies. Also included in this paper is a brief introduction of standards for these pollutants in ambient air or in occupational settings established by the United States Environmental Protection Agency (USEPA), the United States Occupational Safety and Health Administration (OSHA) and the World Health Organization (WHO). The review ends with a summary of the limitations and gaps in recent studies and suggestions for future research in the developing world.

Traffic-related occupational exposures to PM2.5, CO, and VOCs in Trujillo, Peru.

A traffic-related exposure study was conducted among 58 workers (drivers, vendors, traffic police, and gas station attendants) and 10 office workers as controls in Trujillo, Peru, in July 2002. PM2.5 was collected, carbon monoxide (CO) was measured, volatile organic compounds (VOCs) were sampled and analyzed. Newspaper vendors had the highest full-shift CO exposures (mean +/- SD: 11.4 +/- 8.9 ppm), while office workers had the lowest (2.0 +/- 1.7 ppm). Bus drivers had the highest full-shift PM2.5 exposures (161 +/- 8.9 microg/m3), while gas station attendants (64 +/- 26.5 microg/m3) and office workers (65 +/- 8.5 microg/m3) were the lowest. Full-shift benzene/toluene/ethylbenzene/xylene exposures (BTEX) among gas station attendants (111/254/43/214 microg/m3) were much higher than those among van and taxi drivers. Several of the traffic-related occupational exposures studied were elevated and are of occupational health concern.