Opportunities and challenges related to saturation of toxicokinetic processes: Implications for risk assessment

Tan, Yu‐Mei; Barton, Hugh A.; Boobis, Alan R.; Brunner, Rachel; Clewell, Harvey J.; Cope, Rhian B.; Dawson, Jeffrey L.; Domoradzki, Jeanne; Egeghy, Peter; Gulati, Pankaj; Ingle, Brandall; Kleinstreuer, Nicole; Lowe, Kelly; Lowit, Anna; Mendez, Elizabeth; Miller, David; Minucci, Jeffrey M.; Nguyen, James; Paini, Alicia; Perron, Monique M.; Phillips, Katherine A.; Qian, Hua; Ramanarayanan, Tharacad S.; Sewell, Fiona; Villanueva, Philip; Wambaugh, John F.; Embry, Michelle R.

doi:10.1016/j.yrtph.2021.105070

Cited by 13 publications

(6 citation statements)

References 74 publications

(94 reference statements)

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“…For example, agrochemical registration requires a battery of tests in multiple species that cover all life stages ( Sewell et al , 2021 ). These traditional testing approaches run counter to current socioethical calls for a reduction in animal use and limitations on high-dose testing ( Tan et al , 2021 ; US EPA, n.d. ). Furthermore, the time- and resource-intensive nature of current testing practices puts significant limitations on our collective ability to generate data on environmental chemicals needed to protect human health.…”

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confidence: 96%

A Transformative Vision for an Omics-Based Regulatory Chemical Testing Paradigm

Johnson

Auerbach

Stevens

et al. 2022

Toxicological Sciences

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Use of molecular data in human and ecological health risk assessments of industrial chemicals and agrochemicals has been anticipated by the scientific community for many years; however, these data are rarely used for risk assessment. Here, a logic framework is proposed to explore the feasibility and future development of transcriptomic methods to refine and replace the current apical endpoint-based regulatory toxicity testing paradigm. Four foundational principles are outlined and discussed that would need to be accepted by stakeholders prior to this transformative vision being realized. Well-supported by current knowledge, the first principal is that transcriptomics is a reliable tool for detecting alterations in gene expression that result from endogenous or exogenous influences on the test organism. The second principle states that alterations in gene expression are indicators of adverse or adaptive biological responses to stressors in an organism. Principle three is that transcriptomics can be employed to establish a benchmark dose-based point of departure (POD) from short-term, in vivo studies at a dose level below which a concerted molecular change (CMC) is not expected. Finally, principle four states that the use of a transcriptomic POD (set at the CMC dose level) will support a human health-protective risk assessment. If all four principles are substantiated, this vision is expected to transform aspects of the industrial chemical and agrochemical risk assessment process that are focused on establishing safe exposure levels for mammals across numerous toxicological contexts resulting in a significant reduction in animal use while providing equal or greater protection of human health. Importantly, these principals and approach are also generally applicable for ecological safety assessment.

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confidence: 96%

A Transformative Vision for an Omics-Based Regulatory Chemical Testing Paradigm

Johnson

Auerbach

Stevens

et al. 2022

Toxicological Sciences

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“…The replacement approach includes in vitro or in silico methods. Rehnement involves reducing, eliminating, or relieving animais' pain or distress, and thereby improving their well-being (Tan et al, 2021). Additionally, there is a need to change the classical, animal testing-based approach towards more modem tools that are more prédictive for humans.…”

Section: T K T D M O D Elsmentioning

confidence: 99%

A critical review of effect modeling for ecological risk assessment of plant protection products

Larras

Charles

Chaumot

et al. 2022

Environ Sci Pollut Res

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A wide diversity of plant protection products (PPP) is used for crop protection leading to the contamination of soil, water, and air, which can hâve ecotoxicological impacts on living organisms. It is inconceivable to study the effects of each compound on each species from each compartment, experimental studies being time consuming and cost prohibitive, and animal testing having to be avoided. Therefore, numerous models are developed to assess PPP ecotoxicological effects. Our objective was to provide an overview of the modelling approaches enabling the assessment of PPP effects (inc.luding biopesticides) on the biota. Six categories of models were inventoried: QSAR, DR and TKTD, population, multi-species, landscape, and mixture models. They were developed for various species (terrestrial and aquatic vertebrates and invertebrates, primary producers, micro-organisms) belonging to diverse environmental compartments, and address different goals (e.g., species sensitivity or PPP bioaccumulation assessment, ecosystem ser vices protection). Among them, mechanistic models are increasingly recognized by EFSA for P P P regulatory risk assessment but, to date, remain not considered in notified guidance documents. The strengths and limits of the reviewed models are discussed together with improvement avenues (multi-generational effects, multiple biotic and abiotic stressors. ..). This review also underlines a lack of model testing by rneans of fleld data and of sensitivity and uncertainty analyses. Accurate and robust modelling of PPP effects and other stressors on living organisms, from their application in the ffeld to their functional consé quences on the ecosystems at different scales of time and space, would help going towards a more sustainable management of the environment. K e y w o r d s: Ecotoxicological m odels, ecological m odels, risk assessm ent, environm ent, ecotoxicity, m ulti-stressors, E u ro p ea n rég u latio n Review of models for ERA of plant protection products

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“…Current focus includes the regulatory use of PBPK and guidance in the use of TK in repeat dose studies to set dose levels and aid interpretation of dose response study results for chemical risk assessment. Progress has been made in identifying barriers and providing recommendations on the definition of the inflection point, human exposure prediction, 3Rs aspects, pros and cons of integrating TK, and how to integrate the various lines of evidence into an organized weight of evidence framework (Tan et al 2021 ). More areas of development include statistical and PBPK modelling approaches to determine non-linearity in dose response, and the use of new approach methodologies (NAMs) to support dose selection.…”

Section: Meeting the Needs Of Chemical Classificationmentioning

confidence: 99%

Recommendations on dose level selection for repeat dose toxicity studies

Sewell

Green²,

Andrus

et al. 2022

Arch Toxicol

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Prior to registering and marketing any new pharmaceutical, (agro)chemical or food ingredient product manufacturers must, by law, generate data to ensure human safety. Safety testing requirements vary depending on sector, but generally repeat-dose testing in animals form the basis for human health risk assessments. Dose level selection is an important consideration when designing such studies, to ensure that exposure levels that lead to relevant hazards are identified. Advice on dose level selection is provided in test guidelines and allied guidance documents, but it is not well harmonised, particularly for selection of the highest dose tested. This paper further builds on concepts developed in a technical report by the European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) which recommends pragmatic approaches to dose selection considering regulatory requirements, animal welfare and state of the art scientific approaches. Industry sectors have differing degrees of freedom to operate regarding dose level selection, depending on the purpose of the studies and the regulatory requirements/legislation, and this is reflected in the overall recommended approaches. An understanding of systemic exposure should be utilised where possible (e.g., through toxicokinetic approaches) and used together with apical endpoints from existing toxicity studies to guide more appropriate dose level selection. The highest dose should be limited to a reasonable level, causing minimal but evident toxicity to the test animals without significantly compromising their well-being. As the science of predictive human exposure further develops and matures, this will provide exciting and novel opportunities for more human-relevant approaches to dose level selection.

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Opportunities and challenges related to saturation of toxicokinetic processes: Implications for risk assessment

Cited by 13 publications

References 74 publications

A Transformative Vision for an Omics-Based Regulatory Chemical Testing Paradigm

A Transformative Vision for an Omics-Based Regulatory Chemical Testing Paradigm

A critical review of effect modeling for ecological risk assessment of plant protection products

Recommendations on dose level selection for repeat dose toxicity studies

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