Relationship between phthalate exposure and kidney function in Taiwanese adults as determined through covariate-adjusted standardization and cumulative risk assessment.

Few studies have investigated the associations between phthalate exposure and kidney function indicators in adults by simultaneously performing covariate-adjusted creatinine standardization, cumulative risk assessment, and mixture analysis. Thus, we applied these methods simultaneously to investigate the aforementioned associations in an adult population. This cross-sectional study analyzed data (N = 839) from a community-based arm of the Taiwan Biobank. The levels of 10 urinary phthalate metabolites were measured and calculated as the sum of the molar concentrations of the dibutyl phthalate metabolite (ΣDBPm) and di(2-ethylhexyl) phthalate (DEHP) metabolite (ΣDEHPm). The hazard index (HI) and daily intake (DI) were estimated by measuring the urinary levels of the phthalate metabolite. Kidney function biomarkers were assessed by measuring the following: blood urea nitrogen (BUN), uric acid, the albumin-to-creatinine ratio (ACR), and the estimated glomerular filtration rate (eGFR). Generalized linear models were implemented to examine the associations between exposure to individual phthalates, HI scores, and kidney function biomarkers. We also employed Bayesian kernel machine regression (BKMR) to analyze the relationships between exposure to various combinations of phthalates and kidney function. ΣDEHPm levels were significantly and positively associated with BUN and ACR levels, and ΣDBPm levels were positively associated with ACR levels. In addition, eGFR was negatively associated with ΣDBPm and ΣDEHPm levels. In the BKMR model, a mixture of 10 phthalate metabolites was significantly associated with BUN, uric acid, ACR, and eGFR results. Higher DIDEHP and higher DIDnBP values were significantly associated with lower eGFRs and higher ACRs, respectively. Higher DIDiBP and DIDEP values were significantly associated with higher uric acid levels. A higher HI was significantly associated with lower eGFRs and higher ACRs. Our results suggest that exposure to environmental phthalates is associated with impaired kidney function in Taiwanese adults.

Aggregating exposures and toxicity equivalence approach into an integrated probabilistic dietary risk assessment for perchlorate, nitrate, and thiocyanate: Results from the National food monitoring study and National Food Consumption Database.

Perchlorate, nitrate, and thiocyanate, namely thyroid disrupting chemicals (TDCs), are found ubiquitously in the environment, leading to broad human exposure and primary uptake through the food web and drinking water. TDCs are all competitive inhibitors of thyroid iodide uptake activity, but limited studies have assessed the cumulative risk of dietary exposure to multiple TDCs. Thus, in this study, we analyzed the individual exposure risk from 310 food samples in 11 categories, and also assessed the cumulative health risks from TDCs for the Taiwanese population using a perchlorate equivalent concentration (PEC) approach. Consequently, this study not only demonstrated the non-carcinogenic health risks from individual exposure but also highlighted that the cumulative exposure to these TDCs may adversely affect human thyroid functioning. Vegetables, livestock, fruits, and dairy products are the most susceptible to PEC exposure. We highlighted nitrate as the main contributor to PEC exposure. Finally, controlling the overall TDC concentrations from vegetables, livestock, fruits, and dairy products is emphasized in this study. This is the first study to conduct a cumulative risk assessment of dietary exposure to TDCs using the PEC approach for the Taiwanese population through probabilistic and sensitivity analyses.

Pesticide exposure among Czech adults and children from the CELSPAC-SPECIMEn cohort: Urinary biomarker levels and associated health risks.

Current-use pesticides (CUP) are extensively applied in both agricultural and urban settings. Exposure occurs mainly via the dietary pathway; however, other pathways such as inhalation or skin contact are also important. In this study, urinary levels of 12 CUP metabolites were investigated among 110 parent-child pairs during two seasons of 2020. Metabolites of pyrethroids (3-PBA, t/c-DCCA), chlorpyrifos (TCPY), and tebuconazole (TEB-OH) were detected in more than 60% of the samples. Chlorpyrifos metabolite was found at the highest concentration and tebuconazole was detected in almost all samples. CUP urinary metabolite levels were significantly higher in children in comparison to adults, except for tebuconazole, which was similar in both groups. In children, winter samples had significantly higher concentrations of pyrethroid and chlorpyrifos metabolites in comparison to the summer samples, but in adults, only chlorpyrifos metabolite concentrations were higher in the winter. No association between CUP urinary metabolite levels and proximity/surface of agricultural areas around residences was observed. Based on our findings, we suspect that CUP exposure is mainly driven by diet and that the effect of environmental exposure is less significant. Daily Intakes were estimated with three possible scenarios considering the amount of the metabolite excreted in urine and were compared to Acceptable Daily Intake values. Using a realistic scenario, exposure to chlorpyrifos exhibited the highest health risk, but still within a safe level. The Acceptable Daily Intake was exceeded only in one child in the case of cypermethrin. The cumulative risk assessment of pesticide mixtures having an effect on the nervous system, based on the total margin of exposure calculations, did not indicate any risk. The overall risk associated with pesticide exposure in the observed population was low. However, the risk observed using the worst-case scenario suggests the need for continuous evaluation of human exposure to such compounds, especially in children.

Exposure to melamine and its derivatives in Chinese adults: The cumulative risk assessment and the effect on routine blood parameters.

Melamine (MEL) and its derivatives, ammeline (AMN), ammelide (AMD), cyanuric acid (CYA) are widely existed in environmental media. Animal studies have reported the cumulative risk assessment (CRA) of simultaneous exposure to MEL and its derivatives and explored the associations between exposure and routine blood parameters. Such information is largely unknown in human studies. In this study, we detected the urinary concentrations of MEL and its derivatives in 239 Chinese adults to conduct the CRA by evaluating their hazard quotients (HQ) and hazard Index (HI), and also explored the possible associations between exposure and measured routine blood parameters in study population. The detectable frequencies of MEL, AMN, AMD and CYA were 96.65%, 41.00%, 97.91% and 97.07%, respectively. The median values of creatinine (Cr)-adjusted MEL, AMN, AMD, CYA and the total concentrations of MEL and its derivatives (∑MEL) were 11.41 µg/g Cr, not detected (ND), 2.64 µg/g Cr, 15.30 µg/g Cr, 35.02 µg/g Cr, respectively. There were 9 (3.77%) participants with estimated daily intakes (EDIs) of CYA exceeding the tolerable daily intake (TDI) of 2500 ng/kg bw/day, and 12 (5.02%) participants with HI of ∑MEL exposure exceeding 1 based on the strictest TDI value. Urinary concentrations of MEL and its derivatives were positively associated with specific routine blood parameters, including hematocrit, hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin concentration, mean corpuscular hemoglobin, white blood cell, neutrophil count (P < 0.05). Meanwhile, exposure to MEL and its derivatives increased the risk of red blood cell abnormality (P < 0.05). Our study is the first study to provide evidence-based data on the CRA of exposure to MEL and its derivatives in Chinese adults, and to propose a possible association between such exposure and routine blood parameters in human.

Resolving ecosystem complexity in ecological risk assessment for mine site rehabilitation.

CONTEXT: Ecological Risk Assessments (ERAs) are important tools for supporting evidence-based decision making. However, most ERA frameworks rarely consider complex ecological feedbacks, which limit their capacity to evaluate risks at community and ecosystem levels of organisation. METHOD: We used qualitative mathematical modelling to add additional perspectives to previously conducted ERAs for the rehabilitation of the Ranger uranium mine (Northern Territory, Australia) and support an assessment of the cumulative risks from the mine site. Using expert elicitation workshops, separate qualitative models and scenarios were developed for aquatic and terrestrial systems. The models developed in the workshops were used to construct Bayes Nets that predicted whole-of-ecosystem outcomes after components were perturbed. RESULTS: The terrestrial model considered the effect of fire and weeds on established native vegetation that will be important for the successful rehabilitation of Ranger. It predicted that a combined intervention that suppresses both weeds and fire intensity gave similar response predictions as for weed control alone, except for lower levels of certainty to tall grasses and fire intensity in models with immature trees or tall grasses. However, this had ambiguous predictions for short grasses and forbs, and tall grasses in models representing mature vegetation. The aquatic model considered the effects of magnesium (Mg), a key solute in current and predicted mine runoff and groundwater egress, which is known to adversely affect many aquatic species. The aquatic models provided support that attached algae and phytoplankton assemblages are the key trophic base for food webs. It predicted that shifts in phytoplankton abundance arising from increase in Mg to receiving waters, may result in cascading effects through the food-chain. CONCLUSION: The qualitative modelling approach was flexible and capable of modelling both gradual (i.e. decadal) processes in the mine-site restoration and the comparatively more rapid (seasonal) processes of the aquatic ecosystem. The modelling also provides a useful decision tool for identifying important ecosystem sub-systems for further research efforts.

Dissipation and Residue of Metalaxyl-M and Azoxystrobin in Scallions and Cumulative Risk Assessment of Dietary Exposure to Hepatotoxicity.

Metalaxyl-M and azoxystrobin have been used to control various fungal diseases on scallion and other crops. In view of the adverse toxic effects of both on the mammalian liver, it is necessary to conduct a cumulative risk assessment of their dietary exposure to consumers. The residues of metalaxyl-M and azoxystrobin on scallion were determined by a quick, easy, cheap, effective, rugged, and safe method (QuEChERS) combined with high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS). The half-lives were about 1.15 and 3.89 days, respectively, and the final residues after a seven-day harvest interval were <0.001−0.088 mg/kg and 0.190−4.687 mg/kg, respectively. The cumulative dietary risk quotient of the two fungicides to Chinese consumers calculated by the probability model is 13.94%~41.25%. According to the results of the contribution analysis, the risk posed by azoxystrobin is much greater than that of metalaxyl-M. Although metalaxyl-M and azoxystrobin do not pose a cumulative risk to Chinese consumers, the risk to children and adolescents is significantly higher than that to adults. This suggests that in future research, more consideration should be given to the cumulative risk of compounds to vulnerable groups.

Cumulative stressors reduce the self-regulating capacity of coastal ecosystems.

Marine ecosystems are prone to tipping points, particularly in coastal zones where dramatic changes are associated with interactions between cumulative stressors (e.g., shellfish harvesting, eutrophication and sediment inputs) and ecosystem functions. A common feature of many degraded estuaries is elevated turbidity that reduces incident light to the seafloor, resulting from multiple factors including changes in sediment loading, sea-level rise and increased water column algal biomass. To determine whether cumulative effects of elevated turbidity may result in marked changes in the interactions between ecosystem components driving nutrient processing, we conducted a large-scale experiment manipulating sediment nitrogen concentrations in 15 estuaries across a national-scale gradient in incident light at the seafloor. We identified a threshold in incident light that was related to distinct changes in the ecosystem interaction networks (EIN) that drive nutrient processing. Above this threshold, network connectivity was high with clear mechanistic links to denitrification and the role of large shellfish in nitrogen processing. The EIN analyses revealed interacting stressors resulting in a decoupling of ecosystem processes in turbid estuaries with a lower capacity to denitrify and process nitrogen. This suggests that, as turbidity increases with sediment load, coastal areas can be more vulnerable to eutrophication. The identified interactions between light, nutrient processing and the abundance of large shellfish emphasizes the importance of actions that seek to manage multiple stressors and conserve or enhance shellfish abundance, rather than actions focusing on limiting a single stressor.

Accounting for Health Risk Inequality in Regulatory Impact Analysis: Barriers and Opportunities.

There has been increasing interest in accounting for inequality in health risks and benefits within regulatory impact analyses, both given more general interest in the distributions of benefits and growing concerns about inequity (defined as those inequalities deemed unjust or unfair) and environmental injustice (in this context, those health risk inequalities that are correlated with race/ethnicity and certain other sociodemographic factors). Although there has been growing literature on this topic, there has been limited progress in practice, and the lack of quantification limits consideration of inequality in the policy process. Controversy remains regarding the best approaches to formally incorporate inequality, when these approaches should be used, and even whether it makes sense to quantify inequality in this context. The objective of this article is to review the literature on approaches for incorporating estimates of, and concerns for, inequality into regulatory impact analyses, especially those where environmental justice considerations are relevant, and consider the interpretation of these approaches and the implications for decision making. Using the case example of the Transportation and Climate Initiative, a collaboration among Northeast and Mid-Atlantic states to reduce carbon emissions from the transportation sector, multiple strategies are described that could be used to shed light on health risk inequality and inequity, consider them in pending policy decisions, and evaluate their implications for the policy or instrument choice. Given appropriate contextualization and acknowledgment of the multidimensionality of equity, quantitative inequality indicators can provide meaningful insight about both inequality and inequity in health risks.

A flow scheme for cumulative assessment of pesticides for adverse liver effects.

The European Food Safety Authority (EFSA) is developing approaches to cumulative risk assessment by assigning pesticides to cumulative assessment groups (CAGs). For assignment to CAGs, EFSA relies on common toxic effects (CTEs) on the target system. The developed flow scheme for assignment to liver CAGs sequentially assesses the consistency of the CTE, its adversity, its potential to be secondary to other toxicities, its human relevance, and the relation of the NOAEL for the CTE to the overall NOAEL. If the responses to all questions are "yes", allocation to a CAG is supported; "no" stops the process.

Cumulative risk assessment of phthalates in edible vegetable oil consumed by Chinese residents.

BACKGROUND: Phthalates have been widely used as plasticizers in various industries and are widely focused on in the international community as a result of their reproductive toxicity. Exposure of Chinese residents to phthalates via edible vegetable oil occurs often. In the present study, gas chromatography-mass spectrometry was used to detect the two main phthalates bis(2-ethylhexyl) phthalate (DEHP) and dibutyl phthalate (DBP) in four major edible vegetable oil sources: an edible oil blend, soybean oil, peanut oil and rapeseed oil (a total of 1016 samples), as collected throughout China. Furthermore, cumulative risk assessment was used to estimate the reproductive health risk to Chinese residents caused by the phthalates that come from edible vegetable oils. RESULTS: Both phthalates were detected in four major edible vegetable oil sources. The phthalate with the highest detection rate was DBP (13.48%), followed by DEHP (7.78%). The results of the cumulative risk assessment showed that the hazard indices of these two phthalates in edible vegetable oils were less than 1, except in soybean oil. Nevertheless, the two phthalates had the lowest detection rates in soybean oil, which were 1.94% (DEHP) and 5.16% (DBP). In China, contamination levels of phthalates in the soils where oil crops are cultivated have a great influence on the phthalate concentrations in edible vegetable oils. CONCLUSION: It is recommended that Chinese residents who are consuming soybean oil choose well-known brands and regularly change their brand of consumption. The phthalates in edible vegetable oils pose a relatively small reproductive health risk to Chinese residents. © 2019 Society of Chemical Industry.

Regulatory assessment and risk management of chemical mixtures: challenges and ways forward.

This paper summarizes current challenges, the potential use of novel scientific methodologies, and ways forward in the risk assessment and risk management of mixtures. Generally, methodologies to address mixtures have been agreed; however, there are still several data and methodological gaps to be addressed. New approach methodologies can support the filling of knowledge gaps on the toxicity and mode(s) of action of individual chemicals. (Bio)Monitoring, modeling, and better data sharing will support the derivation of more realistic co-exposure scenarios. As knowledge and data gaps often hamper an in-depth assessment of specific chemical mixtures, the option of taking account of possible mixture effects in single substance risk assessments is briefly discussed. To allow risk managers to take informed decisions, transparent documentation of assumptions and related uncertainties is recommended indicating the potential impact on the assessment. Considering the large number of possible combinations of chemicals in mixtures, prioritization is needed, so that actions first address mixtures of highest concern and chemicals that drive the mixture risk. As chemicals with different applications and regulated separately might lead to similar toxicological effects, it is important to consider chemical mixtures across legislative sectors.

Arsenic and fasting blood glucose in the context of other drinking water chemicals: a cross-sectional study in Bangladesh.

GOAL: The goal of this study was to evaluate the association between groundwater arsenic and fasting blood glucose in the context of other groundwater chemicals, in Bangladesh. METHODS: Fasting blood glucose, gender, body mass index, sociodemographic variables, and diabetes medication use were measured among adults ≥ 35 years of age (n = 6587) participating in the Bangladesh Demographic and Health Survey (BDHS) 2011. Groundwater chemicals in 3534 well water samples were measured in the British Geological Survey (BGS) and Department of Public Health Engineering (DPHE) 1998-99 survey. We assigned the nearest BGS-DPHE well's chemical exposure to each BDHS participant. We used survey-estimation linear regression methods to model natural log-transformed fasting blood glucose, among those using groundwater as their primary drinking-water source, as a function of groundwater arsenic. We considered possible interactions between categorical arsenic exposure and each of 14 other groundwater chemicals dichotomized at their medians. The chemicals considered as possible effect modifiers included: aluminum, barium, calcium, iron, potassium, lithium, magnesium, manganese, sodium, phosphorous, silicon, sulfate, strontium, and zinc. RESULTS: Compared to persons exposed to groundwater arsenic ≤ 10 µg/L, the adjusted geometric mean ratio (GMR) of fasting blood glucose was 1.01 (95% confidence interval: 0.98, 1.04) for individuals exposed to groundwater arsenic concentrations > 10 µg/L and ≤ 50 µg/L, and was 1.01 (0.97, 1.03) for those with > 50 µg/L arsenic. There were no Bonferroni-significant interactions with other chemicals, after accounting for the large number of chemicals tested as modifiers. CONCLUSIONS: In our analysis of groundwater chemistry data from 1998/99 and fasting blood glucose outcomes measured in nearby populations approximately a decade later, there was no overall association of fasting blood glucose with nearby historical groundwater arsenic. This null association was not significantly modified by the historical levels of other groundwater chemicals. These null results are inconclusive regarding shorter-term potential toxicity of arsenic for glucose regulation, if there are differences between the historical concentrations measured in nearby groundwater and the actual drinking water chemical exposures in the population during the etiologically relevant period for more acute phenotypes like fasting blood glucose. Drinking water supply-relevant, longitudinal exposure assessment with less measurement error is needed to more precisely evaluate the joint impacts of drinking water chemicals and establish if there is a sensitive time window for glycemic outcomes.

Epidemiologically-informed cumulative risk hypertension models simulating the impact of changes in metal, organochlorine, and non-chemical exposures in an environmental justice community.

Blood pressure is a leading risk factor for cardiovascular disease, influenced by chemical and non-chemical stressors. Exposure reduction strategies can potentially improve public health, but there are analytical challenges in developing quantitative models of health benefits, including the need for detailed multi-stressor exposure models, corresponding health evidence, and methods to simulate changes in exposure and resultant health benefits. These challenges are pronounced in low-income urban communities, where residents are often simultaneously exposed to numerous chemical and non-chemical stressors. For New Bedford (Massachusetts, USA), a low-income community near a Superfund site, we simulated geographically-resolved individual data, and applied previously published structural equation models developed from National Health and Nutrition Examination Survey (NHANES) data. These models simultaneously predict exposures to multiple chemicals (e.g., lead (Pb), cadmium (Cd), and polychlorinated biphenyls (PCBs)) and non-chemical factors (e.g., socioeconomic status), and determine their combined effects on blood pressure. We then modeled counterfactual scenarios reducing exposures and estimated the resulting changes in blood pressure distribution in the community. Results indicated small shifts in mean blood pressure and percentage of normotensive individuals with a reduction of Pb and/or PCB exposure. For example, a reduction in PCB to the lowest 10th percentile exposure in the NHANES resulted in a 2.4 mm Hg shift in systolic blood pressure (SBP), corresponding with 3% fewer individuals with SBP in the Stage 2 hypertension category [SBP ≥140]. Our model also emphasized the importance of the multi-stressor framework by simulating benefits of reductions in smoking rates, given positive associations with Pb and Cd but inverse associations with body mass index and blood pressure. This research demonstrates the ability to jointly consider chemical and non-chemical exposures and their impact on cardiovascular health, using approaches generalizable to other cumulative risk assessment applications.

Urinary levels, composition profile and cumulative risk of bisphenols in preschool-aged children from Nanjing suburb, China.

Due to the extensive use in consumer products, the bisphenols (BPs) pollution in the environments has aggravated and people are frequently exposed to BPs. In this research, four BPs, i.e., bisphenol A (BPA), bisphenol F (BPF), bisphenol S (BPS) and bisphenol AF (BPAF), were determined in urine samples collected from Gaochun District preschool-age children and the concentrations, distribution profiles, potential sources and cumulative risk assessment of the target compounds were studied. Total concentrations of 4 BPs ranged from 2 to 3113.1 ng/L, with the average concentration of 648.6 ng/L. BPA was the predominant congener (accounting for 94%), followed by BPS. Correlation analysis indicated a negative relationship between BPA and BPAF (R = -0.273, p < 0.05). The estimated daily intakes suggested that young females were more sensitive to BPs. Moreover, the cumulative risk for hazard quotient (HQ) of BPA has been evaluated and the results showed that no high risk had occurred. It provided basic information on the occurrence and human exposure to urinary BPs of preschool aged children from Gaochun District.

Burden of disease at the same limit of exposure to airborne polycyclic aromatic hydrocarbons varies significantly across countries depending on the gap in longevity.

Atmospheric polycyclic aromatic hydrocarbons (PAHs) disproportionately affect human health across the globe, and differential exposure is believed to drive the unequal health burden. Therefore, this study assessed and compared the burden of disease, in disability-adjusted life years (DALYs), at the same level (or limit) of exposure to atmospheric PAHs in nine countries. We calculated the DALYs per person-year per ng/m3 of benzo[a]pyrene from ten cancers and thirty-four non-cancer adverse outcomes using published toxicity information and country-specific disease severity. Exposure duration was averaged over 30 years and we adjusted for early-life vulnerability to cancer. The DALYs per person-year per ng/m3 of fifteen other individual PAHs was calculated using relative potency factors, and toxicity factors derived from quantitative structure-activity relationships. We found that even at the same level of exposure to PAHs, the incremental burdens of disease varied substantially across countries. For instance, they varied by about 2-3 folds between Nigeria and the USA. Countries having the lowest longevity had the highest DALYs per person-year per ng/m3 of each PAH. Kruskal-Wallis test (α = 0.05) showed that the variation across countries was significant. The post hoc tests detected a significant difference between two countries when the gap in longevity was >10 years. This suggests that countries having very low average life expectancy require more stringent PAH limit. Linear or exponential function of average longevity gave valid approximation of the DALYs per person-year per ng/m3 of benzo[a]pyrene or phenanthrene, respectively. Furthermore, we used global gridded surface benzo[a]pyrene concentrations and global population dataset for 2007, with spatial resolution of 0.1°â€¯× 0.1°, to calculate the contribution of differential exposures to the estimated DALYs per person-year. We found that in six out of nine countries, differential exposures to PAH contribute less to the estimated health loss than differential severities of the diseases. This indicates that the risk to health from PAHs may be underreported if the severities of the diseases in the countries are not considered.

Overview on legislation and scientific approaches for risk assessment of combined exposure to multiple chemicals: the potential EuroMix contribution.

This article reviews the current legislative requirements for risk assessment of combined exposure to multiple chemicals via multiple exposure routes, focusing on human health and particularly on food-related chemicals. The aim is to identify regulatory needs and current approaches for this type of risk assessment as well as challenges of the implementation of appropriate and harmonized guidance at international level. It provides an overview of the current legal requirements in the European Union (EU), the United States and Canada. Substantial differences were identified in the legal requirements for risk assessment of combined exposure to multiple chemicals and its implementation between EU and non-EU countries and across several regulatory sectors. Frameworks currently proposed and in use for assessing risks from combined exposure to multiple chemicals via multiple routes and different durations of exposure are summarized. In order to avoid significant discrepancies between regulatory sectors or countries, the approach for assessing risks of combined exposure should be based on similar principles for all types of chemicals. OECD and EFSA identified the development of harmonized methodologies for combined exposure to multiple chemicals as a key priority area. The Horizon 2020 project "EuroMix" aims to contribute to the further development of internationally harmonized approaches for such risk assessments by the development of an integrated test strategy using in vitro and in silico tests verified for chemical mixtures based on more appropriate data on potential combined effects. These approaches and testing strategies should be integrated in a scientifically based weight of evidence approach to account for complexity and uncertainty, to improve risk assessment.

Characterizing Risk for Cumulative Risk Assessments.

In assessing environmental health risks, the risk characterization step synthesizes information gathered in evaluating exposures to stressors together with dose-response relationships, characteristics of the exposed population, and external environmental conditions. This article summarizes key steps of a cumulative risk assessment (CRA) followed by a discussion of considerations for characterizing cumulative risks. Cumulative risk characterizations differ considerably from single chemical- or single source-based risk characterization. CRAs typically focus on a specific population instead of a pollutant or pollutant source and should include an evaluation of all relevant sources contributing to the exposures in the population and other factors that influence dose-response relationships. Second, CRAs may include influential environmental and population-specific conditions, involving multiple chemical and nonchemical stressors. Third, a CRA could examine multiple health effects, reflecting joint toxicity and the potential for toxicological interactions. Fourth, the complexities often necessitate simplifying methods, including judgment-based and semi-quantitative indices that collapse disparate data into numerical scores. Fifth, because of the higher dimensionality and potentially large number of interactions, information needed to quantify risk is typically incomplete, necessitating an uncertainty analysis. Three approaches that could be used for characterizing risks in a CRA are presented: the multiroute hazard index, stressor grouping by exposure and toxicity, and indices for screening multiple factors and conditions. Other key roles of the risk characterization in CRAs are also described, mainly the translational aspect of including a characterization summary for lay readers (in addition to the technical analysis), and placing the results in the context of the likely risk-based decisions.

A framework for cumulative risk assessment in the 21st century.

The ILSI Health and Environmental Sciences Institute (HESI) has developed a framework to support a transition in the way in which information for chemical risk assessment is obtained and used (RISK21). The approach is based on detailed problem formulation, where exposure drives the data acquisition process in order to enable informed decision-making on human health safety as soon as sufficient evidence is available. Information is evaluated in a transparent and consistent way with the aim of optimizing available resources. In the context of risk assessment, cumulative risk assessment (CRA) poses additional problems and questions that can be addressed using the RISK21 approach. The focus in CRA to date has generally been on chemicals that have common mechanisms of action. Recently, concern has also been expressed about chemicals acting on multiple pathways that lead to a common health outcome, and non-chemical other conditions (non-chemical stressors) that can lead to or modify a common outcome. Acknowledging that CRAs, as described above, are more conceptually, methodologically and computationally complex than traditional single-stressor risk assessments, RISK21 further developed the framework for implementation of workable processes and procedures for conducting assessments of combined effects from exposure to multiple chemicals and non-chemical stressors. As part of the problem formulation process, this evidence-based framework allows the identification of the circumstances in which it is appropriate to conduct a CRA for a group of compounds. A tiered approach is then proposed, where additional chemical stressors and/or non-chemical modulating factors (ModFs) are considered sequentially. Criteria are provided to facilitate the decision on whether or not to include ModFs in the formal quantitative assessment, with the intention to help focus the use of available resources to have the greatest potential to protect public health.

Aggregating exposures & cumulating risk for semivolatile organic compounds: A review.

Increasingly, health risk assessment is addressing multiple pathway exposures to multiple contaminants. We reviewed aggregated exposure and cumulative risk approaches for contemporary and ubiquitous semivolatile organic compounds (SVOC). We identified 22 studies aggregating exposure pathways, and 31 cumulating risk. Exposure aggregation is based on the addition of pathway-specific doses, using kinetic modeling where it exists, and classic external dose equations otherwise. In most cases, exposure is dominated by a single route or source of exposure - mainly the oral pathway - via dietary or non-dietary exposure. Preferential routes and sources of exposure are influenced by SVOC physical-chemical properties such as vapor pressure. The cumulative risk approach for contaminants is based on dose addition. Simple sum of hazard quotient (Hazard Index: HI) is the most commonly used cumulative risk assessment approach, while Relative Potency Factor (RPF) appeared to the best suited - although this calls for a level of toxicological information that limits the number of compounds that can be studied simultaneously. Where both were performed, moving from HI to more refined approach produced similar results. In conclusion, both approaches - exposure aggregation and cumulative risk - rely on simple assumptions. Nevertheless, they allow uncertainty to be reduced, in comparison with source-by-source or chemical-by-chemical approaches.

Toxicological interactions of pesticide mixtures: an update.

Pesticides can interact with each other in various ways according to the compound itself and its chemical family, the dose and the targeted organs, leading to various effects. The term interaction means situations where some or all individual components of a mixture influence each other's toxicity and the joint effects may deviate from the additive predictions. The various mixture effects can be greatly determined by toxicokinetic and toxicodynamic factors involving metabolic pathways and cellular or molecular targets of individual pesticides, respectively. However, the complexity of toxicological interactions can lead to unpredictable effects of pesticide mixtures. Interactions on metabolic processes affecting the biotransformation of pesticides seem to be by far the most common mechanism of synergism. Moreover, the identification of pesticides responsible for synergistic interactions is an important issue for cumulative risk assessment. Cholinesterase inhibiting insecticides (organophosphates and N-methylcarbamates), triazole fungicides, triazine herbicides, and pyrethroid insecticides are overrepresented in the synergistic mixtures identified so far. Since the limited available empirical evidence suggests that synergisms at dietary exposure levels are rather rare, and experimentally occurred at unrealistic high concentrations, synergism cannot be predicted quantitatively on the basis of the toxicity of mixture components. The prediction of biological responses elicited by interaction of pesticides with each other (or with other chemicals) will benefit from using a systems toxicology approach. The identification of core features of pesticide mixtures at molecular level, such as gene expression profiles, could be helpful to assess or predict the occurrence of interactive effects giving rise to unpredicted responses.