A Toxicokinetic Framework and Analysis Tool for Interpreting Organisation for Economic Co-operation and Development Guideline 305 Dietary Bioaccumulation Tests

Gobas, Frank A.P.C.; Lee, Yung-Shan; Lo, Justin C.; Parkerton, Thomas F.; Letinski, Daniel J.

doi:10.1002/etc.4599

Cited by 24 publications

(41 citation statements)

References 26 publications

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“…Moreover, the eye is extremely vascularized organ, so any long-term contact may allow molecules to enter systemic circulation. The eye itself is sensitive and prone to damage from chemical exposure [48]. We found that NZW rabbits instilled with rEP showed irritation within 1 h that lasted up to 72 h. Notably rEP treatment did not cause any long-term corneal opacity, conjunctival redness, or abnormality of the iris, and therefore, it can be considered as safe for eyes [49].…”

Section: Discussionmentioning

confidence: 80%

Lack of Acute Toxicity and Mutagenicity from Recombinant Epinephelus lanceolatus Piscidin Expressed in Pichia pastoris

Chen

Pan²,

Rajanbabu

et al. 2020

Marine Drugs

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The antimicrobial peptide (AMP) piscidin was identified from Epinephelus lanceolatus and demonstrated to possess antimicrobial and immune-related functions. Supplementation of feed with recombinant Epinephelus lanceolatus piscidin (rEP)-expressing yeast pellets may minimize the excessive use of antibiotics and control pathogens in aquaculture or animal husbandry. However, before implementing rEP as a supplement, it is necessary to understand whether it harbors any toxicity. Since toxicological information on the topic is scarce, the present investigation was carried out to test whether rEP exhibits allergenic and/or toxic effects. In an oral acute toxicity test (OECD 425), Sprague Dawley (SD) rats were administered rEP dissolved in reverse osmosis water, yielding an LD50 > 5000 mg/kg (no observed animal death). The compound was therefore classified as non-toxic by oral administration. In an acute respiratory toxicity test (OECD 403), heads and noses of SD rats were exposed to liquid aerosol for 4 h (the highest concentration that could be administered without causing any animal death), and a lethal concentration (LC50) > 0.88 mg/L was obtained. The mass medium aerodynamics diameter (MMAD) of rEP aerosol particles was 8.18 μm and mass medium aerodynamics diameter (GSD) was 3.04, which meant that 25.90% could enter the airway (<4 μm) of a rat, and 58.06% (<10 μm) could be inhaled by humans. An ocular irritation test (OECD 405) with rEP powder was performed on New Zealand White (NZW) rabbits. Signs of irritation included conjunctival swelling and diffuse flushing 1 h after administration. The signs were less apparent after 24 h and disappeared after 72 h. The classification assigned to the powder was mild eye irritation. Skin sensitization was performed for a local lymphoproliferative test (OECD 442B) using BALB/c mice, with the highest soluble concentration of the rEP considered to be 100% test substance; formulations were diluted to 50% and 25%, and bromodeoxyuridine (BrdU) incorporation was used to measure the degree of lymphocyte proliferation. The stimulation indexes (SIs) were 1.06 (100%), 0.44 (50%), and 0.77 (25%), all of which were less than the cutoff value for a positive sensitization result (1.6). Negative response was also seen in the bacterial reverse mutation test (OECD 471), and no chromosomal effects on Chinese hamster ovary (CHO)-K1 cells were observed (OECD 487). Based on these six toxicity tests, rEP showed neither acute toxic effects in experimental animals nor mutagenicity. Thus, rEP can be considered safe for use in subsequent research on its application as a feed additive for poultry, cattle, or aquatic animals.

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Section: Discussionmentioning

confidence: 80%

Lack of Acute Toxicity and Mutagenicity from Recombinant Epinephelus lanceolatus Piscidin Expressed in Pichia pastoris

Chen

Pan²,

Rajanbabu

et al. 2020

Marine Drugs

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“…The first component was simply plotting the reported BMF L and BMF 5% versus the reported lipid content of the diet. The second component involved analyzing the original experimental concentration–time data in Hashizume et al (2018) of the 2 paired tests using the ADME‐B Calculator (Gobas et al 2019). This was first done for the experiments conducted with the lower–lipid content diet.…”

Section: Methodsmentioning

confidence: 99%

“…This dietary biomagnification model has been incorporated in food web bioaccumulation models and corroborated with thousands of field bioaccumulation metrics (e.g., Arnot and Gobas 2004). The dietary biomagnification model was updated to include intestinal biotransformation and proposed as a toxicokinetic framework for interpreting the results of OECD 305 dietary bioaccumulation tests (Lo et al 2015, 2016; Gobas et al 2019). When updated to include biotransformation in the intestinal tract, the model can be expressed in terms of 2 mass balance equations (i.e., one for the intestinal tract and one for the body of the fish), which in fugacity format, to illustrate the magnification process, are

V_{G} \times Z_{G} \times \frac{{df}_{normalG}}{dt} = D_{D} \times f_{D} + D_{BG} \times f_{B} - (D_{GB} + D_{GE} + D_{GM}) \times f_{G}

V_{B} \times Z_{B} \times \frac{{df}_{normalB}}{dt} = D_{GB} \times f_{G} - (D_{BG} + D_{normalB 2} + D_{BM} + D_{BQ}) \times f_{B}

where f B is fugacity in the body of the fish (pascals), f D is fugacity in the diet (pascals), f G is fugacity in the digesta (pascals), V B is the volume of the body of the fish (cubic meters), V G is the volume of the digesta (cubic meters), Z B is the fugacity capacity of the body of the fish (moles per cubic meter per pascal), Z G is the fugacity capacity of the digesta (moles per cubic meter per pascal), D D is the transport parameter for food ingestion (moles per pascal per day), D GE is the transport parameter for the egestion of digesta from the gastrointestinal tract (moles per pascal per day), D GM is the transport parameter for gastrointestinal biotransformation (moles per pascal per day), D BG is the transport parameter for chemical transfer from the body of the fish to the digesta (moles per pascal per day), D GB is the transport parameter for chemical transfer from the digesta to the body of the fish (moles per pascal per day), D B2 is the transport parameter for chemical transfer from the body of the fish to the water via the respiratory surface (e.g.,...…”

Section: Theorymentioning

confidence: 99%

Normalizing the Biomagnification Factor

Gobas

Lee

Arnot

2020

Environmental Toxicology and Chemistry

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Following a recent proposal of normalizing the experimentally derived biomagnification factor (BMF) to a 5% lipid content in fish, we explore the normalization of the BMF of lipophilic chemicals in fish. We illustrate with theoretical models and experimental data that the BMF of lipophilic chemicals is a function of the lipid content of the diet and that poorly metabolizable, lipophilic chemicals biomagnify in organisms to a greater degree when present in higher-lipid content food. The proposed normalization of the laboratory BMF to the lipid content of the fish and subsequent standardization to a 5% fish lipid content, which is numerically identical to normalizing the BMF to a 5% dietary lipid content, has the potential to underestimate the biomagnification potential of lipophilic substances in aquatic food webs. The BMF normalized to both the lipid content of the fish and the lipid content of the diet, which is the biomagnification metric included in the Organisation for Economic Cooperation and Development's bioaccumulation testing guideline 305, better represents real-world biomagnification than the proposed BMF normalized and standardized to a 5% lipid content in fish.

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“…Data relevance and reliability need to be considered to establish confidence in a chemical assessment. A weight of evidence (WoE) approach (Weed 2005 ; Hope and Clarkson 2014 ; OECD 2019 ; Suter et al 2020 ) can inform B assessment decision‐making given the various metrics and criteria and inherent variability and uncertainty in the underlying data (Barber 2003 ; Burkhard 2003 , 2008; Arnot and Gobas 2006 ; Parkerton et al 2008 ; Crookes and Brooke 2010 ; Borgå et al 2012 ; Burkhard et al 2012 , 2013 ; Arnot and Quinn 2015 ; Gobas et al 2020; Wassenaar et al 2020 ). Indeed, a WoE approach for B assessment is recommended under Annex XIII of the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) legislation in the European Union (EC 2011 ; Moermond et al 2012 ).…”

Section: Introductionmentioning

confidence: 99%

A critical review and weight of evidence approach for assessing the bioaccumulation of phenanthrene in aquatic environments

Armitage

Toose

Camenzuli

et al. 2021

Integr Envir Assess & Manag

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Bioaccumulation (B) assessment is challenging because there are various B‐metrics from laboratory and field studies, multiple criteria and thresholds for classifying bioaccumulative (B), very bioaccumulative (vB), and not bioaccumulative (nB) chemicals, as well as inherent variability and uncertainty in the data. These challenges can be met using a weight of evidence (WoE) approach. The Bioaccumulation Assessment Tool (BAT) provides a transparent WoE assessment framework that follows Organisation for Economic Co‐operation and Development (OECD) principles for performing a WoE analysis. The BAT guides an evaluator through the process of data collection, generation, evaluation, and integration of various lines of evidence (LoE) (i.e., B‐metrics) to inform decision‐making. Phenanthrene (PHE) is a naturally occurring chemical for which extensive B and toxicokinetics data are available. A B assessment for PHE using the BAT is described that includes a critical evaluation of 74 measured in vivo LoE for fish and invertebrate species from laboratory and field studies. The number of LoE are reasonably well balanced across taxa (i.e., fish and invertebrates) and the different B‐metrics. Additionally, in silico and in vitro biotransformation rate estimates and corresponding model‐predicted B‐metrics are included as corroborating evidence. Application of the BAT provides a consistent, coherent, and scientifically defensible WoE evaluation to conclude that PHE is not bioaccumulative (nB) because the overwhelming majority of the bioconcentration, bioaccumulation, and biomagnification metrics for both fish and invertebrates are below regulatory thresholds. An analysis of the relevant data using fugacity ratios is also provided, showing that PHE does not biomagnify in aquatic food webs. The critical review identifies recommendations to increase the consistency of B assessments, such as improved standardization of B testing guidelines, data reporting requirements for invertebrate studies, and consideration of temperature and salinity effects on certain B‐metrics. Integr Environ Assess Manag 2021;17:911–925. © 2021 Concawe. Integrated Environmental Assessment and Management published by Wiley Periodicals LLC on behalf of Society of Environmental Toxicology & Chemistry (SETAC)

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A Toxicokinetic Framework and Analysis Tool for Interpreting Organisation for Economic Co-operation and Development Guideline 305 Dietary Bioaccumulation Tests

Cited by 24 publications

References 26 publications

Lack of Acute Toxicity and Mutagenicity from Recombinant Epinephelus lanceolatus Piscidin Expressed in Pichia pastoris

Lack of Acute Toxicity and Mutagenicity from Recombinant Epinephelus lanceolatus Piscidin Expressed in Pichia pastoris

Normalizing the Biomagnification Factor

A critical review and weight of evidence approach for assessing the bioaccumulation of phenanthrene in aquatic environments

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