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Use of the Species Sensitivity Distribution Approach to Derive Ecological Threshold of Toxicological Concern (eco-TTC) for Pesticides.

ABSTRACT: The species sensitivity distribution (SSD) calculates the hazardous concentration at which 5% of species (HC₅) will be potentially affected. For many compounds, HC₅ values are unavailable impeding the derivation of SSD curves. Through a detailed bibliographic survey, we selected HC₅ values (from acute toxicity tests) for freshwater aquatic species and 129 pesticides. The statistical distribution and variability of the HC₅ values within the chemical classes were evaluated. Insecticides are the most toxic compounds in the aquatic communities (HC₅ = 1.4 × 10^-3 µmol L^-1), followed by herbicides (HC₅ = 3.3 × 10^-2 µmol L^-1) and fungicides (HC₅ = 7.8 µmol L^-1). Subsequently, the specificity of the mode of action (MoA) of pesticides on freshwater aquatic communities was investigated by calculating the ratio between the estimated baseline toxicity for aquatic communities and the HC₅ experimental values gathered from the literature. Moreover, we proposed and validated a scheme to derive the ecological thresholds of toxicological concern (eco-TTC) of pesticides for which data on their effects on aquatic communities are not available. We proposed eco-TTCs for different classes of insecticides, herbicides, and fungicides with a specific MoA, and three eco-TTCs for those chemicals with unavailable MoA. We consider the proposed approach and eco-TTC values useful for risk management purposes.

SUBMITTER: Rizzi C

PROVIDER: S-EPMC8623465 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundThreshold of Toxicological Concern (TTC) approaches are used for chemical safety assessment and risk-based priority setting for data poor chemicals. TTCs are derived from in vivo No Observed Effect Level (NOEL) datasets involving an external administered dose from a single exposure route, e.g., oral intake rate. Thus, a route-specific TTC can only be compared to a route-specific exposure estimate and such TTCs cannot be used for other exposure scenarios such as aggregate exposures.ObjectiveDevelop and apply a method for deriving internal TTCs (iTTCs) that can be used in chemical assessments for multiple route-specific exposures (e.g., oral, inhalation or dermal) or aggregate exposures.MethodsChemical-specific toxicokinetics (TK) data and models are applied to calculate internal concentrations (whole-body and blood) from the reported administered oral dose NOELs used to derive the Munro TTCs. The new iTTCs are calculated from the 5th percentile of cumulative distributions of internal NOELs and the commonly applied uncertainty factor of 100 to extrapolate animal testing data for applications in human health assessment.ResultsThe new iTTCs for whole-body and blood are 0.5 nmol/kg and 0.1 nmol/L, respectively. Because the iTTCs are expressed on a molar basis they are readily converted to chemical mass iTTCs using the molar mass of the chemical of interest. For example, the median molar mass in the dataset is 220 g/mol corresponding to an iTTC of 22 ng/L-blood (22 pg/mL-blood). The iTTCs are considered broadly applicable for many organic chemicals except those that are genotoxic or acetylcholinesterase inhibitors. The new iTTCs can be compared with measured or estimated whole-body or blood exposure concentrations for chemical safety screening and priority-setting.SignificanceExisting Threshold of Toxicological Concern (TTC) approaches are limited in their applications for route-specific exposure scenarios only and are not suitable for chemical risk and safety assessments under conditions of aggregate exposure. New internal Threshold of Toxicological Concern (iTTC) values are developed to address data gaps in chemical safety estimation for multi-route and aggregate exposures.

Project description:Benzimidazoles act by disrupting microtubule polymerisation and are capable of inducing the formation of micronuclei. Considering the similarities in their mechanisms of action (inhibition of microtubule assembly by binding to the colchicine-binding site on tubulin monomers), combination effects according to the principles of concentration addition might occur. If so, it is to be expected that several benzimidazoles contribute to micronucleus formation even when each single one is present at or below threshold levels. This would have profound implications for risk assessment, but the idea has never been tested rigorously. To fill this gap, we analysed micronucleus frequencies for seven benzimidazoles, including the fungicide benomyl, its metabolite carbendazim, the anthelmintics albendazole, albendazole oxide, flubendazole, mebendazole and oxibendazole. Thiabendazole was also tested but was inactive. We used the cytochalasin-blocked micronucleus assay with CHO-K1 cells according to OECD guidelines, and employed an automated micronucleus scoring system based on image analysis to establish quantitative concentration-response relationships for the seven active benzimidazoles. Based on this information, we predicted additive combination effects for a mixture of the seven benzimidazoles by using the concepts of concentration addition and independent action. The observed effects of the mixture agreed very well with those predicted by concentration addition. Independent action underestimated the observed combined effects by a large margin. With a mixture that combined all benzimidazoles at their estimated threshold concentrations for micronucleus induction, micronucleus frequencies of ~15.5% were observed, correctly anticipated by concentration addition. On the basis of independent action, this mixture was expected to produce no effects. Our data provide convincing evidence that concentration addition is applicable to combinations of benzimidazoles that form micronuclei by disrupting microtubule polymerisation. They present a rationale for grouping these chemicals together for the purpose of cumulative risk assessment.

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Use of the Species Sensitivity Distribution Approach to Derive Ecological Threshold of Toxicological Concern (eco-TTC) for Pesticides.

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