Chemical Toxicity Distributions Research Articles

Determination of aquatic hazard concentrations for the oil spill response product class of surface washing agents using species sensitivity distributions

Surface washing agents (SWAs) are a diverse class of oil spill response products intended to facilitate removal of stranded oil from shorelines. This class of agents has high application rates relative to other categories of spill response products, but global toxicity data is generally limited to two standard test species: inland silverside and mysid shrimp. Here, we provide a framework to maximize the utility of limited toxicity data across a product class. To characterize species sensitivity to SWAs, the toxicity of three agents spanning a range of chemical and physical properties were tested in eight species. The relative sensitivity of mysids shrimp and inland silversides as surrogate test organisms was determined. Toxicity normalized species sensitivity distributions (SSDn) were used to estimate fifth centile hazard concentration (HC5) values for SWAs with limited toxicity data. Chemical toxicity distributions (CTD) of SWA HC5 values were used to compute a fifth centile chemical hazard distribution (HD5) to provide a more comprehensive assessment of hazard across a spill response product class with limited toxicity data than traditional single species or single agent approaches can give.

Comparative influences of dermal and inhalational routes of exposure on hazards of cleaning product ingredients among mammalian model organisms.

Health risks resulting from dermal or inhalational exposures are frequently assessed based on rodent oral toxicity information due to a lack of species- or route-specific toxicity data. Default uncertainty factors (UFs; e.g., 10-fold) are also applied during risk assessments to account for variability such as inter-species, intra-species, exposure duration, dose-response, and route-to-route extrapolations. However, whether rodent oral data and a default UF approach can provide adequate protection for other mammalian species under dermal or inhalational exposure scenarios remains understudied, particularly for cleaning product ingredients. Therefore, we collated and examined publicly available median lethal dose (LD50), no-observed-adverse-effect level (NOAEL) and lowest-observed-adverse-effect level (LOAEL) values from different types of standard mammalian toxicity studies for rats (dermal and inhalational), mice, rabbits, guinea pigs, and dogs (oral, dermal and inhalational) using the Cleaning Product Ingredient Safety Initiative (CPISI) database. Probabilistic hazard assessments using chemical toxicity distributions (CTDs) were subsequently conducted, and threshold concentrations (TCs) and 95% confidence intervals (95% CIs) were derived to identify thresholds of toxicological concern (TTCs). Relative sensitivities among or between mammalian species, exposure routes, and chemical classes were also compared based on calculated TC5s and 95% CIs to support future toxicology studies and hazard and risk assessments. We then identified uncertainty factors (UFs) using both CTD comparisons and individual UF probability distributional approaches. Based on available rodent inhalational data, chemical category-specific UFs were derived for ethers. Additionally, we also determined whether default UFs of 10 or 100 would be protective for various distributions of cleaning product ingredients. Our novel observations among these routes of exposure and common mammalian model organisms appear particularly useful for read across and screening-level health hazard and risk assessments when limited data exists for specific chemicals.

Life stage and endpoint sensitivity differences of fathead minnow (Pimephales promelas) to chemicals with various modes of action

Fish Embryo Acute Toxicity (FET) test was proposed as an alternative to the traditional test methods using larval or adult fish. However, whether fathead minnow (Pimephales promelas) embryo is appropriate for FET remains uncertain. In the present study, ecological threshold of toxicological concern (ecoTTC) values and uncertainty factors (UFs) for each Verhaar et al. category in P. promelas were identified by employing probabilistic ecological risk assessment (PERA) approach with chemical toxicity distributions (CTDs). The sensitivity among different life stages and toxicity among different mode of actions (MOAs) classes were comprehensively compared by CTD comparisons. The results showed that embryo exhibited the less or similar sensitivity compared to larva or adult for Verhaar et al. MOA classes (1-4) while adults were more sensitive, followed by embryo than larval for non-classified chemicals. Considering growth effect as endpoint to class 1, class 3, and non-classified chemicals on P. promelas embryo and larva was more sensitive than mortality. Non-classified chemicals especially inorganic compounds were most toxic to P. promelas embryo for the four concerned Verharr et al. MOA-specific chemical classes. This study also derived uncertainty factors (UFs) as 26.5 (9.8, 109) for embryo-to-larva, 6.26 (3.94, 11.0) for embryo-to-adult, 15.6 (10.1, 36.1) for mortality-to-growth, and 3.03 (1.86, 7.08) for mortality-to-reproduction, which can be applied for extrapolations of life stage-to-life stage and effect-to-effect to reduce the underestimating and overestimating risk by the use of default UF such as 10, 100 or 1000. Our findings are vital for feasibility of FET test of P. promelas for ecotoxicity testing and ecological risk assessment for chemicals with different MOAs.

Cumulative impact assessment of hazardous ionic liquids towards aquatic species using risk assessment methods

In the present research work, a comprehensive tool for cumulative ecotoxicological impact assessment of ionic liquids (ILs) to aquatic life has been constructed. Using the probabilistic tool, impact of individual ILs to a group of aquatic species is assessed by chemical toxicity distributions (CTDs). The impact of group of ILs to individual aquatic species is assessed by species sensitivity distributions (SSDs). Acute toxicity data of imidazolium ILs with chloride (Cl−), bromide (Br−), tetrafluoroborate (BF4−), and hexafluorophosphate (PF6−) anions are used in CTD and SSD. Allowable concentrations for a group of Imidazolium ILs with the same mode of action (SMOA) to five aquatic species; Daphnia magna, Vibrio fischeri, Algae, Zebrafish, and Escherichia coli are estimated by CTDs. It has been concluded that 1-Butyl-3-methylimidazolium chloride (BMIMCl) possess the lowest risk at an acceptable risk value of 750 × 10−5 mmol/L which is 12% less than that of OMIMCl. Furthermore, the sensitivities towards the aquatic species reveal that from the studied ILs, BMIMBF4 with an acceptable risk value of 3200 × 10−5 mmol/L is the most suitable IL towards the selected aquatic species. Hence, current work provides cumulative allowable concentrations and acceptable risk values for ILs which release to aquatic compartment of ecosystem.

Balancing chemical function with reduced environmental health hazards: A joint probability approach to examine antimicrobial product efficacy and mammalian toxicity

The fourth principle of Green Chemistry, a critically important area of sustainability science, identifies that substances should maintain intended functions while possessing limited intrinsic hazards to public health and the environment. In the present study, we empirically determined efficacy of 20 cleaning products against E. coli attachment to surfaces. Subsequently, probabilistic assessments using novel chemical efficacy distributions (CEDs) were conducted. Results for most chemicals indicated bacterial detachment with increasing concentration. Using a threshold concentration of 5th centiles, these cleaning product ingredients were predicted to detach E. coli (Lowest Observable Effect Concentration) at or below 0.7 (0.2, 2.2) mg L−1 for 5% of ingredients. We then employed chemical toxicity distributions (CTDs) to examine acute toxicity, based on currently available information, for common mammalian models. Results demonstrate that probabilities of associated hazards for rat (oral exposure route), mouse (oral exposure route), rabbit (dermal exposure route), and rat (inhalation exposure route) were 43.2%, 36.7%, 38.6% and 75.5%, respectively. A novel joint probability distribution analysis approach was then developed and applied to identify substances with various efficacy (CED) and hazard (CTD) characteristics. Our observations indicate that combining efficacy and toxicity information using joint probability curves may be useful for identifying classes of antimicrobial products, and other chemical classes, to optimize efficacy while minimizing environment and health hazards.

One uncertainty factor does not fit all: Identifying mode of action and species specific acute to chronic ratios for aquatic life

In ecological risk assessment, acute to chronic ratio (ACR) uncertainty factors are routinely applied to acute mortality benchmarks to estimate chronic toxicity thresholds. To investigate variability of aquatic ACRs, we first compiled and compared 56 and 150 pairs of acute and subchronic/chronic growth/reproductive toxicity data for fishes (Pimephales promelas (53), Danio rerio (2), and Oryzias latipes (1)) and the crustacean Daphnia magna, respectively, for 172 chemicals with different modes of action (MOA). We found that there were only significant relationships between P. promelas acute median lethal concentrations and growth lowest-observed effect concentrations for class 1 (nonpolar narcosis) chemicals, though significant relationships were demonstrated for D. magna to all Verhaar et al. MOA classes (Class 1: nonpolar narcosis, Class 2: polar narcosis, Class 3: reactive chemicals, and Class 4: AChE inhibitors and estrogenics). Probabilistic ecological hazard assessment using chemical toxicity distributions was subsequently employed for each MOA class to estimate acute and chronic thresholds, respectively, to identify MOA and species specific ecological thresholds of toxicological concern. Finally, novel MOA and species specific ACRs using both chemical toxicity distribution comparison and individual ACR probability distribution approaches were identified using representative MOA and chemical categories. Our data-driven approaches and newly identified ACR values represent robust alternatives to application of default ACR values, and can also support future research and risk assessment and management activities for other chemical classes when toxicity information is limited for chemicals with specific MOAs within invertebrates and fish.

Application of new statistical distribution approaches for environmental mixture risk assessment: A case study.

ObjectivesThere is growing evidence that single substances present below their individual thresholds of effect may still contribute to combined effects. In component-based mixture risk assessment (MRA), the risks can be addressed using information on the mixture components. This is, however, often hampered by limited availability of ecotoxicity data. Here, the possible use of ecotoxicological threshold concentrations of no concern (i.e. 5th percentile of statistical distribution of ecotoxicological values) is investigated to fill data gaps in MRA.MethodsFor chemicals without available aquatic toxicity data, ecotoxicological threshold concentrations of no concern have been derived from Predicted No Effect Concentration (PNEC) distributions and from chemical toxicity distributions, using the EnviroTox tool, with and without considering the chemical mode of action. For exposure, chemical monitoring data from European rivers have been used to illustrate four realistic co-exposure scenarios. Based on those monitoring data and available ecotoxicity data or threshold concentrations when no data were available, Risk Quotients for individual chemicals were calculated, to then derive a mixture Risk Quotient (RQmix).ResultsA risk was identified in two of the four scenarios. Threshold concentrations contribute from 24 to 95% of the whole RQmix; thus they have a large impact on the predicted mixture risk. Therefore they could only be used for data gap filling for a limited number of chemicals in the mixture. The use of mode of action information to derive more specific threshold values could be a helpful refinement in some cases.

Comparative mammalian hazards of neonicotinoid insecticides among exposure durations

Neonicotinoid insecticides have become one of the most widely used insecticides over the past two decades. Recent studies have shown considerable risk of neonicotinoids to beneficial insects, however, their health risks to mammals are still under debate. Limited empirical mammalian toxicity information for neonicotinoids inherently presents challenges to environmental health practitioners performing health hazard and risk assessment. Therefore, we first compiled and examined publicly available hazard data for neonicotinoids, and knowledge gaps on mammals were identified. Probabilistic hazard assessment using chemical toxicity distributions (CTDs) was subsequently conducted, and initial thresholds of toxicological concern were derived for rat, dog, mouse, and rabbit under comparative experimental scenarios. Using the rat model, for example, oral 5% threshold concentrations (TC5s) of 0.11 (0.02, 0.36) and 0.23 (0.001, 3.2) mg/kg bw/day were estimated using chronic developmental and reproductive no observed adverse effect levels (NOAELs), respectively, while acute TC5 of 0.71 (0.25, 1.6) mg/kg bw/day was identified using neurological NOAELs. Comparatively, dermal and inhalational TC5s were estimated as 1583 (1172, 1777) and 451 (294, 615) mg/kg bw/day (equivalent to 486 (322, 622) mg/m3), respectively, using acute median lethal doses. Uncertainty factors (UFs) were also estimated using both CTD comparisons and individual UF probability distribution approaches to test whether rodent oral toxicity information or default 10-fold UF approach can provide sufficient protection for mammals. These initially identified UFs were generally smaller than default values (e.g., 10) employed by regulatory stakeholders, yet larger UFs were occasionally noted. Our findings appear particularly useful for environmental health practitioners when conducting screening-level risk assessment for neonicotinoids, and provide an example for health hazard assessment of pesticides with limited toxicity information.

Probabilistic ecotoxicological risk assessment of imidazolium ionic liquids with amino acid and halide anions

Ionic liquids (ILs) are chemical substances with good solubility and low vapor pressure because they are ionized and therefore charged. ILs may damage ecosystem due to their good water solubility. Toxicological studies for individual ILs. Major constraint in ILs ecotoxicology is that risk cannot be quantified by risk quotient methods because of unavailability of exposure assessment data. At present, only limited information is available about the impacts of ILs to aquatic ecosystems. The main objective of the current work is to use statistical methods to available literature on acute toxicity data of ILs to assess potential ecotoxicological risks when the ILs do come into industrial use. Probabilistic ecotoxicological risk assessment (PETRA) method was adopted by using Chemical Toxicity Distributions (CTDs) and Species Sensitivity Distributions (SSDs). SSDs has been used to derive threshold values below which the ecosystem and its biotic components could be protected from the adverse effect of ILs. CTDs has been used to estimate the probability of finding ILs with an effect below a calculated concentration which is considered to be safe environmental concentration. Acute toxicity data were collected from the literature on the acute toxicity of four bacterial pathogens Aeromonas hydrophila, Escherichia coli, Listeria monocytogenes and Staphylococcus aureus. CTD method was applied to assess the distribution of toxicities of group of IL to individual species. The SSD method was applied to estimate guideline values (GVs) to estimate different level of protection of bacterial species from ILs. Imidazolium chloride and bromide ILs were reported to pose more than 5 % risk towards bacteria. Out of the four bacterial strains, E coli was reported to be potentially at higher risk because of highest sensitivity when exposed towards ILs. The risk posed was five percent which is acceptable level of risk.

Comparative endpoint sensitivity of in vitro estrogen agonist assays

Environmental and human health implications of endocrine disrupting chemicals (EDCs), particularly xenoestrogens, have received extensive study. In vitro assays are increasingly employed as diagnostic tools to comparatively evaluate chemicals, whole effluent toxicity and surface water quality, and to identify causative EDCs during toxicity identification evaluations. Recently, the U.S. Environmental Protection Agency (USEPA) initiated ToxCast under the Tox21 program to generate novel bioactivity data through high throughput screening. This information is useful for prioritizing chemicals requiring additional hazard information, including endocrine active chemicals. Though multiple in vitro and in vivo techniques have been developed to assess estrogen agonist activity, the relative endpoint sensitivity of these approaches and agreement of their conclusions remain unclear during environmental diagnostic applications. Probabilistic hazard assessment (PHA) approaches, including chemical toxicity distributions (CTD), are useful for understanding the relative sensitivity of endpoints associated with in vitro and in vivo toxicity assays by predicting the likelihood of chemicals eliciting undesirable outcomes at or above environmentally relevant concentrations. In the present study, PHAs were employed to examine the comparative endpoint sensitivity of 16 in vitro assays for estrogen agonist activity using a diverse group of compounds from the USEPA ToxCast dataset. Reporter gene assays were generally observed to possess greater endpoint sensitivity than other assay types, and the Tox21 ERa LUC BG1 Agonist assay was identified as the most sensitive in vitro endpoint for detecting an estrogenic response. When the sensitivity of this most sensitive ToxCast in vitro endpoint was compared to the human MCF-7 cell proliferation assay, a common in vitro model for biomedical and environmental monitoring applications, the ERa LUC BG1 assay was several orders of magnitude less sensitive than MCF-7. These observations highlight the importance of employing multiple assays with various molecular initiation and signaling events to inform selection, application, and interpretation of in vitro endpoint responses during future environmental diagnostic applications.

Application of chemical toxicity distributions to ecotoxicology data requirements under REACH

The European Union's REACH regulation has further highlighted the lack of ecotoxicological data for substances in the marketplace. The mandates under REACH (registration, evaluation, authorization, and restriction of chemicals) to produce data and minimize testing on vertebrates present an impetus for advanced hazard assessment techniques using read-across. Research in our group has recently focused on probabilistic ecotoxicological hazard assessment approaches using chemical toxicity distributions (CTDs). Using available data for chemicals with similar modes of action or within a chemical class may allow for selection of a screening point value (SPV) for development of environmental safety values, based on a probabilistic distribution of toxicity values for a specific endpoint in an ecological receptor. Ecotoxicity data for acetylcholinesterase inhibitors and surfactants in Daphnia magna and Pimephales promelas were gathered from several data sources, including the U.S. Environmental Protection Agency's ECOTOX and Pesticides Ecotoxicity databases, the peer-reviewed literature, and the Human and Environmental Risk Assessment (HERA) project. Chemical toxicity distributions were subsequently developed, and the first and fifth centiles were used as SPVs for the development of screening-predicted no-effect concentrations (sPNECs). The first and fifth centiles of these distributions were divided by an assessment factor of 1,000, as recommended by REACH guidance. Use of screening values created using these techniques could support the processes of data dossier development and environmental exposure assessment, allowing for rigorous prioritization in testing and monitoring to fill data gaps.

An initial probabilistic hazard assessment of oil dispersants approved by the united states national contingency plan

Dispersants are commonly applied during oil spill mitigation efforts; however, these industrial chemicals may present risks to aquatic organisms individually and when mixed with oil. Fourteen dispersants are listed on the U.S. Environmental Protection Agency (U.S. EPA) National Oil and Hazardous Substances Pollution Contingency Plan (NCP). Availability of environmental effects information for such agents is limited, and individual components of dispersants are largely proprietary. Probabilistic hazard assessment approaches including Chemical Toxicity Distributions (CTDs) may be useful as an initial step toward prioritizing environmental hazards from the use of dispersants. In the present study, we applied the CTD approach to two acute toxicity datasets: NCP (the contingency plan dataset) and DHOS (a subset of NCP listed dispersants reevaluated subsequent to the Deepwater Horizon oil spill). These datasets contained median lethal concentration (LC50) values for dispersants alone and dispersant:oil mixtures, in two standard marine test species, Menidia beryllina and Mysidopsis bahia. These CTDs suggest that dispersants alone are generally less toxic than oil. In contrast, most dispersant:oil mixtures are more toxic than oil alone. For the two datasets (treated separately because of differing methodologies), CTDs would predict 95% of dispersant:oil mixtures to have acute toxicity values above 0.32 and 0.76 mg/L for Mysidopsis and 0.33 mg/L and 1.06 mg/L for Menidia (for DHOS and NCP, respectively). These findings demonstrate the utility of CTDs as a means to evaluate the comparative ecotoxicity of dispersants alone and in mixture with different oil types. The approaches presented here also provide valuable tools for prioritizing prospective and retrospective environmental assessments of oil dispersants.

Probabilistic ecological hazard assessment of parabens using Daphnia magna and Pimephales promelas

Parabens are common antimicrobial agents found in thousands of pharmaceuticals and personal care products. Parabens are introduced into aquatic ecosystems from wastewater treatment plant effluents and have been detected in surface waters in the low microgram per liter range. Although these compounds display low toxicity in mammals, paraben toxicity to aquatic organisms has not been investigated. Standardized acute and subchronic endpoints in larval fish (Pimephales promelas) and cladoceran (Daphnia magna) models were examined for seven different parabens (methyl-, ethyl-, isopropyl-, propyl-, isobutyl-, butyl-, benzylparaben), which encompassed a range of log P values. Paraben 48 h median lethal concentration values (LC50) ranged from 4.0 to 24.6 mg/L in D. magna and 3.3 to >160.0 mg/L in fathead minnow. Growth and reproduction in D. magna had lowest-observed-effect concentrations (LOECs) ranging from 0.12 to 9.0 mg/L and 1.5 to 6.0 mg/L, respectively. Fathead minnow growth was adversely affected at levels ranging from 1.0 to 25.0 mg/L. Aquatic toxicity of the parabens was inversely related to lipophilicity, suggesting that responses using standardized endpoints resulted from narcosis. Utilizing toxicity benchmark concentrations (e.g., LC50s, LOECs) for each compound, chemical toxicity distributions, a probabilistic hazard assessment technique, were developed to assess the probabilities of detecting parabens that elicit a response at or below a given concentration. For the responses assessed in the present study, the 5th centile values (the concentration at which 5% of parabens elicit a response) ranged from 15 microg/L to 2.43 mg/L, with D. magna growth eliciting the lowest 5th centile value and acute D. magna mortality eliciting the highest. The distributions demonstrated that at environmentally relevant concentrations in developed countries there is limited acute or subchronic aquatic hazard of parabens to the organisms and responses examined.

Comparison of the sensitivities of common in vitro and in vivo assays of estrogenic activity: Application of chemical toxicity distributions

A number of contaminants in municipal effluent discharges are estrogen agonists to fish. Whereas several in vitro and in vivo techniques have been developed to assess the estrogenic activity of these compounds or ambient environmental samples, previous comparisons of the relative sensitivities of these approaches remain inconclusive. We employed a probabilistic hazard assessment approach using chemical toxicity distributions (CTDs) to perform a novel evaluation of relative sensitivities of six common in vitro and in vivo assays. We predicted that there was an 8.3% (human breast ademocarcinoma cell line, MCF-7, assay), 6.3% (yeast estrogen screen assay), or 1.9% (fish hepatocyte vitellogenin, VTG, assay) probability of detecting a compound in aquatic systems that will elicit an estrogenic response at concentrations at or below 0.1 microg/L, suggesting that the MCF-7 assay was the most sensitive in vitro assay evaluated in this study. The probabilities of eliciting the estrogenic response of VTG induction at a concentration less than 0.1 microg/L in rainbow trout, fathead minnow, and Japanese medaka were determined at 29.9, 26.2, and 18.8%, respectively. Thus, rainbow trout VTG induction was the most sensitive in vivo assay assessed. Subsequently, CTDs may provide a useful technique for hazard assessment of chemical classes for which exposure data are limited and for chemicals with common toxicological mechanisms and modes of action.

Probabilistic ecological hazard assessment: Evaluating pharmaceutical effects on aquatic higher plants as an example

The practicality of a probabilistic ecological hazard assessment (PEHA) methodology using intraspecies endpoint sensitivity distributions (IESDs) and chemical toxicity distributions (CTDs) was evaluated on data sets of pharmaceutical toxicity to aquatic macrophytes. A PEHA does not use an exposure distribution but rather uses a point estimate, which is useful for applications with sufficient effects data but lacking in comprehensive exposure data or when a criterion concentration is desired. The probability of finding an effect measure or potency value below a threshold can be calculated from the effects distribution. PEHA analyses using CTDs for both EC 10 and EC 25 Lemna gibba toxicity values indicated a <1% probability of encountering an antibiotic with toxicity below 1 μg/L. IESDs for microcosm mixture studies with eight pharmaceuticals (8PM) and four tetracyclines showed that the probability was nearly 20% for Myriophyllum sibiricum and 13% for L. gibba (8PM data). Hazard quotients calculated from the 1% and 5% distribution thresholds indicated potential risk only in certain cases.