Developmental toxicity of polychlorinated biphenyls (PCBs): a systematic review of experimental data

Experimental reproductive and developmental toxicity studies with polychlorinated biphenyls (PCBs) are reviewed in brief to determine their relevance for current environmental exposure of humans during the prenatal and postnatal developmental periods. Additional material is published in electronic form only, which contains graphic overviews on individual PCBs and various mixtures that are linked with the relevant citations. In this comprehensive article we focus on interactions of PCBs with biological substrates that could mediate adverse effects observed in experimental animals and in children, and the shortcomings of many of the animal studies available. A main point of criticism involves the relative lack of animal data on several of those persistent congeners, either as individual compounds or as environmentally relevant mixtures, which are currently used as a measure of human exposure. Experimental studies in animals are frequently conducted with commercial PCB mixtures, a test design that does not reflect the exposure situation in humans. Important improvements of animal experiments could be achieved by more complete reporting of litter data (pre- and post-natal losses, toxic signs in the dam and the offspring, birth weights and postnatal growth data), the inclusion of endpoints that have been found previously to be affected by PCBs, and measurements of internal exposure data.An erratum to this article can be found at     

Environmental distribution,transport and ecotoxicity of microplastics: A review

Microplastics (MPs) have become a global environmental pollutant because of their unique properties. The extensive MP toxicity reports have focused on the aquatic environment, while the pervasive MP contamination in the soil and air has largely been overlooked. This review summarizes the abundance, sources and transport of MPs in different environments. It analyzes the toxicity of MPs based on various environmentally relevant bacterial, cellular, plant, aquatic animal and mammalian test groups, using both in vitro and in vivo experiments. The combined toxicity effects of MPs and various other environmental pollutants on ecosystems are also discussed. Currently, data on the adverse effects on combined MP toxicity are very limited. Thus, a systematic assessment of the environmental risk in different environments and in various species from MPs is challenging. Thus, this review proposes the possible risks and identifies the knowledge gaps posed by MPs to food safety and human health.     

A New Interpretation of Avian and Mammalian Reproduction Toxicity Test Data in Ecological Risk Assessment

The long-term risks of pesticides to wildlife in the EU currently are assessed by comparing the lowest no-observed-effect concentration (NOEC) determined from the suite of endpoints measured in existing avian and mammalian laboratory reproduction tests with estimated exposure concentrations by calculating Toxicity to Exposure Ratios (TERs). Regulatory authorities experience difficulties when assessing long-term risks because of the lack of accepted methods to improve the ecological realism of exposure and toxicity estimates and understand risks at a population level. This paper describes an approach for interpreting existing avian and mammalian toxicity test data that divides breeding cycles into several discrete phases and identifies specific test endpoints as indicators of direct pesticide effects possible at each phase. Based on the distribution of breeding initiation dates for a species of concern and the dates of pesticide applications, this approach compares the phase-specific toxicity endpoint with the expected pesticide exposure levels during each of the breeding phases. The fate of each breeding attempt is determined through a series of decision points. The cumulative reproductive response of individuals in a breeding population based on this decision framework provides a means of examining the estimated risks over the course of the breeding season and deriving an overall metric of the impact of the pesticide on reproduction. Research needed to further improve the approach is discussed.     

氯仿的毒理学研究现状及氯仿残留的风险性评估

目的为氯仿残留的毒理学研究及风险评估工作提供参考,以预防和控制其危害。方法整理分析国内外相关法规和文献。结果与结论从6个方面综合介绍了氯仿毒理学研究现状及风险性评估研究进展。     

Derivation of inhalation toxicity reference values for propylene oxide using mode of action analysis: Example of a threshold carcinogen

Propylene oxide (PO) is an important industrial chemical used primarily in the synthesis of other compounds. Inhalation carcinogenesis studies in rodents, with no-observed-adverse-effect levels (NOAELs) of 100 and 200?ppm, have revealed that chronic, high exposure to PO can induce tumors at the site of contact. Despite these characteristics, there is no evidence that typical environmental or occupational exposures to PO constitute a health risk for humans. The nongenotoxic effects of PO (glutathione depletion and cell proliferation) that augment its DNA-reactive and non-DNA-reactive genotoxicity are expected to be similar in humans and rodents. Available evidence on mode-of-action suggests that cancer induction by PO at the site of contact in rodents is characterized by a practical threshold. Human toxicity reference values for potential carcinogenic effects of PO were derived based on nasal tumors identified in rodent studies and specified uncertainty factors. The 95% lower confidence limit on the dose producing a 10% increase in additional tumor risk (LED10) was calculated using the rat and mouse data sets. The human reference values derived from the rat and mouse LED10 values were 0.7 and 0.5?ppm PO, respectively. A similar noncancer reference value, 0.4?ppm, was derived on the basis of non-neoplastic nasal effects in rats.     

Multiple Stressor Effects on Benthic Biodiversity of Chesapeake Bay: Implications for Ecological Risk Assessment

In natural aquatic systems, there is frequently overlap in the spatial distribution of both natural and anthropogenic stressors, particularly at regional geographic scales. Yet the proportional risk associated with individual stressors, their cumulative effects and the manner in which they interact to affect aquatic ecology is frequently unknown, limiting the robustness of multiple-stressor ecological risk assessments (ERA). The current study used historical environmental monitoring data (1984–1999) to identify a combination of natural and anthropogenic stressors that best accounted for observed patterns of benthic biodiversity in Chesapeake Bay. Geographic information systems (GIS) were used to geographically link spatially heterogeneous databases for benthic biodiversity, water quality and sediment toxicant concentrations. Single and multiple variable regression techniques were subsequently used to develop a statistical model to explain observed patterns of benthic biodiversity. Combinations of natural stressors alone accounted for as much as 34% of the variation in benthic biodiversity, and combinations of anthropogenic toxicants accounted for as much as 48% of the variation. The consideration of both natural and anthropogenic stressors resulted in a statistical model that accounted for approximately 73% of the observed variation in benthic biodiversity of Chesapeake Bay. These results suggest that benthic biodiversity in Chesapeake Bay is a function of complex interactions among water quality characteristics and anthropogenic toxicants. Therefore, new risk assessment methodologies are required to assess the risk of multiple stressors at regional scales.     

正己烷的毒理学研究现状及风险评估

正己烷作为溶剂在工业中的广泛应用已导致多起职业性中毒的发生。为预防和控制其危害,本文从六个方面综合介绍了正己烷毒理学研究现状及风险评估研究进展。     

Incorporation of the biomarker concept in ecotoxicology calls for a redefinition of terms

Biomarkers have received a lot of attention but the biomarker concept has not yet been defined properly. As a consequence, various interpretations of the term biomarker exist, some of which overlap with well-established ecotoxicological concepts. To allow incorporation of the biomarker concept within the framework of modern ecotoxicology, a clarification of terms is needed. In this paper, definitions are presented for the terms biomarker, bioindicator and ecological indicator, which do not overlap and are linked to different levels of biological organization. The use of these concepts for ecological effects assessment is discussed.     

Tropical ecotoxicity testing with Ceriodaphnia cornuta

The Sai Gon-Dong Nai river system in southern Vietnam is of great social and economic importance yet receives a large amount of industrial, domestic, and agricultural discharges. Toxicity assessment has started to become an issue in Vietnam, and it is important to employ a test system that is appropriate for typical Vietnamese conditions with a species that is representative of the invertebrates living in its aquatic ecosystems. The aim of this study was to develop and to validate an ecotoxicity test with an autochthonous organism. The microcrustacean Ceriodaphnia cornuta (Cladocera) was isolated from the Sai Gon River. A protocol was developed for the culturing of the organisms, and satisfactory results were obtained for long-term reproduction of C. cornuta. Quality control criteria were established. The toxicity of two relevant pesticides (diazinon and methyl parathion) and two metals (chromium and mercury) to C. cornuta was evaluated and compared to the standard organisms for ecotoxicological testing: Daphnia magna and Vibrio fischeri. Nonlinear regression models were applied to estimate such parameters as EC(50). The results of acute toxicity tests showed that C. cornuta was less tolerant than D. magna and V. fischeri to salinity and that C. cornuta was more sensitive than D. magna and V. fischeri to potassium dichromate, diazinon, methyl parathion, and mercury.     

Grouping of carbonaceous nanomaterials based on association of patterns of inflammatory markers in BAL fluid with adverse outcomes in lungs

Abstract

Carbonaceous nanomaterials (CNMs) are universally being used to make commodities, as they present unique opportunities for development and innovation in the fields of engineering, biotechnology, etc. As technology advances to incorporate CNMs in industry, the potential exposures associated with these particles also increase. CNMs have been found to be associated with substantial pulmonary toxicity, including inflammation, fibrosis, and/or granuloma formation in animal models. This study attempts to categorize the toxicity profiles of various carbon allotropes, in particular, carbon black, different multi-walled carbon nanotubes, graphene-based materials, and their derivatives. Statistical and machine learning-based approaches were used to identify groups of CNMs with similar pulmonary toxicity responses from a panel of proteins measured in bronchoalveolar lavage (BAL) fluid samples and with similar pathological outcomes in the lungs. Thus, grouped particles, based on their pulmonary toxicity profiles, were used to select a small set of proteins that could potentially identify and discriminate between the toxicity profiles associated within each group. Specifically, MDC/CCL22 and MIP-3β/CCL19 were identified as common protein markers associated with both toxicologically distinct groups of CNMs. In addition, the persistent expression of other selected protein markers in BAL fluid from each group suggested their ability to predict toxicity in the lungs, i.e. fibrosis and microgranuloma formation. The advantages of such approaches can have positive implications for further research in toxicity profiling.     

Improving the scientific foundation for mixtures joint toxicity and risk assessment: contributions from the SOT mixtures project--introduction

Risk assessments are enhanced when policy and other decision-makers have access to experimental science designed to specifically inform key policy questions. Currently, our scientific understanding and science policy for environmental mixtures are based largely on extrapolating from and combining data in the observable range of single chemical toxicity to lower environmental concentrations and composition, i.e., using higher dose data to extrapolate and predict lower dose toxicity. There is a growing consensus that the default assumptions underlying those mixtures risk assessments that are conducted in the absence of actual mixtures data rest on an inadequate scientific database. Future scientific research should both build upon the current science and advance toxicology into largely uncharted territory. More precise approaches to better characterize toxicity of mixtures are needed. The Society of Toxicology (SOT) sponsored a series of panels, seminars, and workshops to help catalyze and improve the design and conduct of experimental toxicological research to better inform risk assessors and decision makers. This paper summarizes the activities of the SOT Mixtures Program and serves as the introductory paper to a series of articles in this issue, which hope to inspire innovative research and challenge the status quo.     

Variability of in vivo fish acute toxicity data

The variability of toxicity data contained within databases was investigated using the widely used US EPA ECOTOX database as an example. Fish acute lethality (LC50) values for 44 compounds (for which at least 10 data entries existed) were extracted from the ECOTOX database yielding a total of 4654 test records. Significant variability of LC50 test results was observed, exceeding several orders of magnitude. In an attempt to systematically explore potential causes of the data variability, the influence of biological factors (such as test species or life stages) and physical factors (such as water temperature, pH or water hardness) were examined. Even after eliminating the influence of these inherent factors, considerable data variability remained, suggesting an important role of factors relating to technical and measurement procedures. The analysis, however, was limited by pronounced gaps in the test documentation. Of the 4654 extracted test reports, 66.5% provided no information on the fish life stage used for testing. Likewise, water temperature, hardness or pH were not recorded in 19.6%, 48.2% and 41.2% of the data entries, respectively. From these findings, we recommend the rigorous control of data entries ensuring complete recording of testing conditions. A more consistent database will help to better discriminate between technical and natural variability of the test data, which is of importance in ecological risk assessment for extrapolation from laboratory tests to the field, and also might help to develop correction factors that account for systematic differences in test results caused by species, life stage or test conditions.     

Quantity and quality of natural organic matter influence the ecotoxicity of titanium dioxide nanoparticles

Nanoparticles’ fate is amongst other parameters determined by the quantity and quality of natural organic matter (NOM). Consequently, the ecotoxicity of nanoparticles is modified, while only little information is available on the NOM characteristics triggering this interplay. This study systematically examined how NOM quantity and quality influences the acute ecotoxicity of titanium dioxide nanoparticles (nTiO₂) towards Daphnia magna. Therefore, two nTiO₂ products (A-100 and P25; ～100?nm) were investigated in combination with seven NOM types of variable quality at four levels each (up to 4.00?mg total organic carbon/L). The results showed that – independent of the applied nTiO₂ product and NOM type – nTiO₂ ecotoxicity decreased up to a factor of?>18 with increasing NOM concentration. More importantly, increasing levels of aromaticity and hydrophobicity of the NOM decreased the magnitude of toxic effects caused by nTiO₂, which was again independent of the nTiO₂ product tested. In the light of the ubiquitary presence of NOM, the ecotoxicological risk of nTiO₂ in surface waters with high NOM loads is likely moderate. However, interactions of nTiO₂ and NOM in combination with other natural or chemical stressors are not well-understood but seem to be fundamental for a reliable risk assessment of nanoparticles.     

A survey of frameworks for best practices in weight-of-evidence analyses

Abstract

The National Academy of Sciences (NAS) Review of the Environmental Protection Agency’s Draft IRIS Assessment of Formaldehyde proposed a “roadmap” for reform and improvement of the Agency’s risk assessment process. Specifically, it called for development of a transparent and defensible methodology for weight-of-evidence (WoE) assessments. To facilitate development of an improved process, we developed a white paper that reviewed approximately 50 existing WoE frameworks, seeking insights from their variations and nominating best practices for WoE analyses of causation of chemical risks. Four phases of WoE analysis were identified and evaluated in each framework: (1) defining the causal question and developing criteria for study selection, (2) developing and applying criteria for review of individual studies, (3) evaluating and integrating evidence and (4) drawing conclusions based on inferences. We circulated the draft white paper to stakeholders and then held a facilitated, multi-disciplinary invited stakeholder workshop to broaden and deepen the discussion on methods, rationales, utility and limitations among the surveyed WoE frameworks. The workshop developed recommendations for improving the conduct of WoE evaluations. Based on the analysis of the 50 frameworks and discussions at the workshop, best practices in conducting WoE analyses were identified for each of the four phases. Many of these best practices noted from the analysis and workshop could be implemented immediately, while others may require additional refinement as part of the ongoing discussions for improving the scientific basis of chemical risk assessments.     

Multivariate analysis of the impacts of the turbine fuel JP-4 in a microcosm toxicity test with implications for the evaluation of ecosystem dynamics and risk assessment

Turbine fuels are often the only aviation fuel available in most of the world. Turbine fuels consist of numerous constituents with varying water solubilities, volatilities and toxicities. This study investigates the toxicity of the water soluble fraction (WSF) of JP-4 using the Standard Aquatic Microcosm (SAM). Multivariate analysis of the complex data, including the relatively new method of nonmetric clustering, was used and compared to more traditional analyses. Particular emphasis is placed on ecosystem dynamics in multivariate space.The WSF is prepared by vigorously mixing the fuel and the SAM microcosm media in a separatory funnel. The water phase, which contains the water-soluble fraction of JP-4 is then collected. The SAM experiment was conducted using concentrations of 0.0, 1.5 and 15% WSF. The WSF is added on day 7 of the experiments by removing 450 ml from each microcosm including the controls, then adding the appropriate amount of toxicant solution and finally bringing the final volume to 3 L with microcosm media. Analysis of the WSF was performed by purge and trap gas chromatography. The organic constituents of the WSF were not recoverable from the water column within several days of the addition of the toxicant. However, the impact of the WSF on the microcosm was apparent. In the highest initial concentration treatment group an algal bloom ensued, generated by the apparent toxicity of the WSF of JP-4 to the daphnids. As the daphnid populations recovered the algal populations decreased to control values. Multivariate methods clearly demonstrated this initial impact along with an additional oscillation seperating the four treatment groups in the latter segment of the experiment. Apparent recovery may be an artifact of the projections used to describe the multivariate data. The variables that were most important in distinguishing the four groups shifted during the course of the 63 day experiment. Even this simple microcosm exhibited a variety of dynamics, with implications for biomonitoring schemes and ecological risk assessments.     

Risk Assessment of Shellfish Toxins

Complex secondary metabolites, some of which are highly toxic to mammals, are produced by many marine organisms. Some of these organisms are important food sources for marine animals and, when ingested, the toxins that they produce may be absorbed and stored in the tissues of the predators, which then become toxic to animals higher up the food chain. This is a particular problem with shellfish, and many cases of poisoning are reported in shellfish consumers each year. At present, there is no practicable means of preventing uptake of the toxins by shellfish or of removing them after harvesting. Assessment of the risk posed by such toxins is therefore required in order to determine levels that are unlikely to cause adverse effects in humans and to permit the establishment of regulatory limits in shellfish for human consumption. In the present review, the basic principles of risk assessment are described, and the progress made toward robust risk assessment of seafood toxins is discussed. While good progress has been made, it is clear that further toxicological studies are required before this goal is fully achieved.     

药物毒性数据库与监管科学

药物毒性数据库的开发和计算毒理学新模型研究已逐渐成为21世纪药物毒性评价的新范式.通过数据挖掘技术和计算机预测技术,可以快速了解、分析和评估药物毒性、作用机制或暴露特征等相关信息.药物毒性数据的分析与预测结果也成为支持药品研发或监管决策的重要新手段.世界发达国家许多毒理研究机构都开发和建立了各自特点的毒理学数据库.本文...     

An integrated addition and interaction model for assessing toxicity of chemical mixtures.

The high propensity for simultaneous exposure to multiple environmental chemicals necessitates the development and use of models that provide insight into the toxicity of chemical mixtures. In this study, we developed a mathematical model that combines concepts of concentration addition, response addition, and toxicokinetic chemical interaction to assess toxicity of chemical mixtures. A ternary mixture of acetylcholinesterase inhibiting organophosphates (malathion and parathion) and the P450 inhibitor piperonyl butoxide was used to model toxicity. Concentration-response curves were generated for individual chemicals as well as for mixtures of the chemicals using acute toxicity tests with Daphnia magna. The toxicity of binary combinations of malathion and parathion adhered to the principles of concentration addition. The contribution of piperonyl butoxide to mixture toxicity was integrated using a model for response addition. Piperonyl butoxide also modified the toxicity of the organophosphates by inhibiting their metabolic activation. The antagonistic effects of piperonyl butoxide towards the organophosphates were quantified as coefficients of interactions (K-functions) and incorporated into the mixture model. Finally, toxicity of the ternary mixture was modeled at 30 different mixture formulations using three additive models that assumed no interaction (concentration addition, response addition, and integrated addition) and using the integrated addition and interaction (IAI) model. Toxicity of the 30 mixtures was then experimentally determined and compared to model results. Only the IAI model accurately predicted the toxicity of the mixtures. The IAI model holds promise as a means for assessing hazard of complex chemical mixtures.     

Evaluation of neurobehavioral abnormalities and immunotoxicity in response to oral imidacloprid exposure in domestic chickens (Gallus gallus domesticus)

ABSTRACT

Domestic chickens (Gallus gallus domesticus) were exposed to imidacloprid by gavage once daily for 7 consecutive days at 0, 0.03, 0.34, 3.42, 10.25, and 15.5 mg/kg/day (n = 20 per group; 5 6-week-old males, 5 6-week-old females, 5 9-week-old males, and 5 9-week-old females). The severity and duration of neurobehavioral abnormalities were recorded. Components of the innate and adaptive immune system were assessed with 7 standard functional assays. Temporary neurobehavioral abnormalities were observed in a dose-dependent manner, including muscle tremors, ataxia, and depressed mentation. Based upon mean clinical severity scores, the no observed adverse effect level (NOAEL) was 3.42 mg/kg/day, and the lowest observed adverse effect level (LOAEL) was 10.25 mg/kg/day. The effective dose value for the presence of any neurobehavioral abnormalities in 50% of the test group (ED₅₀) was 4.62 ± 0.98 mg/kg/day. The ED₅₀ for an adjusted score that included both severity and duration of neurobehavioral abnormalities was 11.24 ± 9.33 mg/kg/day. These ED₅₀ values are equivalent to a 1 kg bird ingesting 29 or 70 imidacloprid treated soybean seeds respectively. Immunotoxicity was not documented, possible causes include the assays were insensitive, relevant immune functions were not examined, or imidacloprid is not immunotoxic at this dosing schedule in this species. Neurobehavioral abnormalities were a more sensitive indicator of the sublethal effects of imidacloprid than immunotoxicity.     

Sensitivity analyses for informative censoring in survival data: A trial example

In a controlled clinical trial comparing an experimental drug to a control using time to event analysis, the logrank test is normally used to test against the equality between two survival curves when the proportional hazard rate assumption is held, which of course requires non-informative censoring. The authors used an example from a randomized, double-blind, parallel group, low-dose active controlled study comparing the safety and efficacy of two doses (400 mg/day versus 50 mg/day) of study medication used as monotherapy for the treatment of newly diagnosed or recurrent epilepsy. This analysis imputes the event time of subjects considered to have problematic informative censoring to demonstrate the impact of violations in necessary assumptions, and assesses robustness of the p-value as calculated from imputed data as compared with un-imputed data. Assuming a parametric distribution for time to event, had these subjects resulted in an event in the trial after withdrawal, the expected additional time to event is formulated and calculated using methods developed in this article. Combining the imputed informative censoring subjects with the remainder of the original data, new p-values are obtained using the log-rank test and compared to the original p-value. KM plots are also compared.