Method for constructing physiological toxicokinetic model of organic pollutants in East Asian Jiangguinea pigs

Abstract

The invention belongs to the field of environmental toxicology research and application, and relates to a construction method of a physiological toxicokinetic model of organic pollutants in East Asian cowfish bodies. Comprising the following steps: determining the kinetic process of absorption, distribution, metabolism and excretion of organic pollutants in East Asian cowfish bodies; determining an atrioventricular composition structure of the physiological toxicokinetic model of the organic pollutants in the East Asian cowfish; establishing an in-vivo organic pollutant content change differential equation of the East Asian cowfish; acquiring and collecting model parameters: physiological parameters of East Asian Jiangguinea pigs, biochemical parameters of organic pollutants and toxicokinetic parameters of the organic pollutants; and solving and verifying the model. Compared with other models, the model adopts real physiological parameters of species, has higher prediction accuracy and has the potential of cross-species extrapolation among marine mammals. The model has a very wide development prospect in the field of environmental toxicology, and can gradually replace animal experiments to become an important means for ecological toxicology research of pollutants.

Description

Technical Field

[0001] The invention belongs to the field of environmental toxicology research and application, and relates to a method for constructing a physiological toxicokinetic model of organic pollutants in East Asian finless porpoises. Background Art

[0002] Organic pollutants can be released into the environment throughout the life cycle of chemicals and enter the marine system through multi-media transport pathways such as atmospheric dry and wet deposition, surface runoff, and biogeochemical cycles. This makes the ocean a key medium for assessing the long-term environmental fate and ecological effects of organic pollutants. The continuously increasing organic pollutant load in the marine environment will lead to an increasing amount of organic pollutants deposited in deep-sea sediments and entering aquatic food webs. Some organic pollutants, due to their resistance to natural degradation, can persist in the environment for decades and enter polar and deep-sea environments through long-distance transport. Studies have reported that concentrations of organic pollutants in deep-sea organisms are higher than those in nearby surface waters. In the marine environment, organic pollutants not only reduce seawater quality but also cause habitat destruction for marine organisms, leading to reduced species richness in the ocean. After entering marine organisms such as plankton and invertebrates, organic pollutants can bioaccumulate and biomagnify within the aquatic food chain.

[0003] Organic pollutants transmitted through the food chain can ultimately accumulate in marine mammals, which are at the top of the marine food chain. Long-term exposure can affect their immune and reproductive systems, threatening their health and survival over the long term, leading to population declines or even population collapse, and ultimately causing irreversible damage to the biodiversity of marine ecosystems. The survival of marine mammals, particularly cetaceans, provides an indicative indicator of the overall state of the marine ecosystem. Due to their relatively long lifespans and physiological characteristics, such as their rich lipid content, marine mammals are exposed to a variety of marine organic pollutants throughout their lives, resulting in the highest exposure of all marine wildlife. Research indicates that approximately 60% of marine mammal species are threatened by pollution, making it the second-most significant threat to marine biodiversity after fishery bycatch. Studies have shown that polybrominated diphenyl ethers (PBDEs) can cause liver toxicity and thyroid hormone-interfering toxic effects in marine mammals, and can cause certain damage to the immune system. Pathological studies and pollutant analyses of accidentally caught and stranded harbor porpoises (Phocoena phocoena) have also shown that atrophy and damage to immune organs such as the thymus and spleen of harbor porpoises are significantly associated with elevated concentrations of polychlorinated biphenyls (PCBs) and PBDEs in their bodies. Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are immunotoxic to walruses (Odobenus rosmarus) and bottlenose dolphins (Tursiops truncatus), increasing their susceptibility to disease.

[0004] Clarifying the accumulation trends of typical organic pollutants in marine mammals is of great significance for assessing the survival status of marine mammals and the health of marine ecosystems. However, marine mammal samples are often difficult to obtain, and experimental testing alone cannot accurately reflect the absorption, distribution, metabolism, and excretion processes of pollutants in marine mammals after exposure to organic pollutants, namely the ADME process, and cannot effectively correlate environmental concentrations with internal exposure concentrations. Although traditional toxicokinetics (TK) models can be used to establish mathematical models based on experimental measurements to predict the toxicokinetics processes of organic pollutants in organisms, due to the lack of physiological relevance, it is difficult to accurately predict the internal exposure concentrations of biological target organs.

[0005] Physiologically based toxicokinetics (PBTK) models follow the law of conservation of mass and abstract the physiologically or anatomically significant tissues or organs in an organism into compartments connected by the blood circulation system. Taking into account the physicochemical and biochemical properties of the pollutant itself, they quantitatively describe the ADME process of the pollutant in the organism, thereby linking the environmental exposure concentration of the pollutant with the target concentration in the body and achieving accurate prediction of the accumulated concentration at the tissue and organ level. The establishment of a PBTK model generally involves five steps: (1) determining the kinetic process of the pollutant in the body; (2) establishing the compartment structure of the model; (3) converting it into a mathematical model; (4) defining the model parameter values; and (5) solving and validating the model.

[0006] Currently, there have been some successful cases using the PBTK model to predict temporal trends in pollutant levels in aquatic animals. However, most studies focus on the accumulation of a single pollutant at the individual level or using two-compartment models. Studies examining the exposure of top predators, such as marine mammals, to multiple organic pollutants across different sexes are lacking. Currently, there is a lack of physiological toxicokinetic models that demonstrate sex-specific accumulation of multiple organic pollutants throughout life in the East Asian finless porpoise. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a physiological toxicokinetic model of organic pollutants in East Asian finless porpoises with gender differences and a construction method thereof, so as to realize the prediction of the accumulation trend of organic pollutants in multiple tissues and organs of East Asian finless porpoises of different genders during their life span.

[0008] The technical solution of the present invention:

[0009] A method for constructing a physiological toxicokinetic model of organic pollutants in East Asian finless porpoises comprises the following steps:

[0010] Step (1) determining the kinetics of absorption, distribution, metabolism, and excretion of organic pollutants in the East Asian finless porpoise, i.e., ADME processes;

[0011] Step (2) establishing the compartmental structure of the physiological toxicokinetics PBTK model based on the ADME process of organic pollutants in the East Asian finless porpoise;

[0012] Step (3) establishing the differential equations describing the dynamic processes of organic pollutants in each compartment in the PBTK model;

[0013] Step (4) obtaining and collecting model parameters;

[0014] Step (5) solves the model to obtain the relationship between the accumulation of organic pollutants in each compartment and time.

[0015] The kinetic process includes: the first step, absorption. Theoretically, the ways in which organic pollutants are absorbed by organisms include respiratory exposure, skin exposure, and ingestion exposure, among which ingestion exposure is the most common way for marine mammals such as the East Asian finless porpoise to absorb organic pollutants. The second step is distribution. After organic pollutants enter the body of the East Asian finless porpoise, they are widely distributed in various tissues in the body, with the kidneys, liver, brain tissue, and other tissues as target organs. The third step is metabolism. Organic pollutants are metabolized in the body of the East Asian finless porpoise in the form of an elimination half-life. The fourth step is excretion. Lipophilic organic pollutants are filtered and reabsorbed more efficiently in the glomeruli and renal tubules, and the amount excreted in the urine is negligible.

[0016] The physiological toxicokinetic model compartment structure includes the kidney, liver, brain tissue, and other tissues, each of which is connected by the blood circulation system. Other tissues represent tissues and organs that are not designated as independent compartments in the model structure, such as the heart, spleen, and muscle.

[0017] Combining the physiological parameter data obtained through anatomical experiments with the physiological parameters, biochemical parameters, and toxicokinetic parameters collected from literature and databases, the corresponding mathematical differential equations for each tissue organ compartment are listed and solved.

[0018] The present invention is based on a constructed PBTK model of organic pollutants. By detecting the levels of organic pollutants in the kidneys, liver, brain tissue, and other tissues, the present invention can obtain the actual exposure values ​​of each compartment in the body. By detecting the levels of organic pollutants in predatory fish, the actual exposure values ​​in vitro can be obtained. By correlating the environmental concentration with the internal exposure concentration through the model, the metabolic kinetic process of organic pollutants can be more clearly described from the perspective of physiological structure, and a PBTK-based internal and external exposure correlation model of organic pollutants can be obtained.

[0019] In summary, the physiological toxicokinetic model of organic pollutants established in this invention, by correlating the dietary exposure dose with the internal exposure accumulation level, makes it possible to estimate the internal accumulation level by monitoring the dietary exposure dose in vitro. Based on the physiological differences between male and female individuals, by constructing a physiological toxicokinetic model to predict the accumulation trend of organic pollutants throughout the lifespan of East Asian finless porpoises of different sexes, a clearer understanding of the lifelong accumulation trend of organic pollutants in multiple compartments can be obtained, providing a scientific basis for formulating species-specific conservation strategies and assessing regional ecological risks.

[0020] Beneficial effects of the present invention:

[0021] This study has developed a sex-specific physiological toxicokinetic model for organic pollutants in East Asian finless porpoises (E. finless porpoises). This model effectively predicts the lifetime accumulation of organic pollutants in E. finless porpoises. Compared to other models, this model utilizes species-specific physiological parameters, resulting in higher predictive accuracy and the potential for cross-species extrapolation among marine mammals. This model holds great promise for the development of environmental toxicology and could gradually replace animal experiments as a key tool for studying the ecotoxicology of pollutants. BRIEF DESCRIPTION OF THE DRAWINGS

[0022] Figure 1 It is the basic flow chart of the present invention.

[0023] Figure 2 It is a compartmental structure diagram of the physiological toxicokinetic model of East Asian finless porpoise constructed by the present invention.

[0024] Figure 3 This is the comparison result between the physiological toxicokinetic model prediction and the measured data of male East Asian finless porpoise.

[0025] Figure 4 This is the comparison result between the physiological toxicokinetic model prediction and the measured data of female East Asian finless porpoise. DETAILED DESCRIPTION

[0026] The specific implementation of the present invention is further described below in conjunction with the accompanying drawings and technical solutions.

[0027] This embodiment provides a prediction model for the lifetime accumulation trend of organic pollutants in East Asian finless porpoises and a method for constructing the same. The overall process of the method of the present invention is as follows: Figure 1 shown.

[0028] (1) Determine the absorption, distribution, metabolism, and excretion kinetics of organic pollutants in different compartments, namely, ADME processes:

[0029] East Asian finless porpoises ingest organic pollutants through predation. These pollutants, assimilated with food, first enter the liver, then flow through the liver's venous blood into the circulatory system. They are then distributed to various compartments of the body, where they undergo metabolic transformation and are partially eliminated. Because most organic pollutants are lipophilic, they are more efficiently filtered and reabsorbed by the glomeruli and renal tubules. Actual urine samples from East Asian finless porpoises are unavailable, so in the model, excreted organic pollutants are integrated into liver metabolism.

[0030] (2) Establish the compartmental structure of the physiological toxicokinetic model of organic pollutants in East Asian finless porpoises:

[0031] use Figure 2 The compartment structure shown in the model divides the East Asian finless porpoise into four compartments: liver, kidney, brain and other tissues.

[0032] (3) Establish the model differential equation describing the kinetic process of organic pollutants:

[0033] Based on the principles of blood flow rate limitation and mass conservation, a mass balance differential equation was developed to describe the ADME process of organic pollutants in each compartment of the East Asian finless porpoise. The mass conservation differential equation describes the change in the organic pollutant content within a compartment, namely: the change in the amount of substance in a compartment per unit time = the instantaneous mass of the substance flowing into the compartment with arterial blood - the instantaneous mass of the substance flowing out of the compartment with venous blood + the substance generation term in that compartment - the substance elimination term in that compartment.

[0034] Change rate of total organic pollutants in the liver (ng / h):

[0035]

[0036] Among them: A L is the amount of organic pollutants accumulated in the liver (ng); t is the accumulation time of organic pollutants (h); Q L is the blood perfusion of the liver (L / h); C b is the concentration of organic pollutants in blood (ng / L); C L is the concentration of organic pollutants in the liver (ng / L); P L:b is the liver-blood partition coefficient of the organic pollutant, dimensionless; ADI is the amount of organic pollutant that enters the liver after ingestion (ng / h); RAM is the clearance rate of organic pollutants in the liver (ng / h);

[0037] Change rate of total organic pollutants in kidney (ng / h):

[0038]

[0039] Among them: A K is the amount of organic pollutants accumulated in the kidney (ng); t is the accumulation time of organic pollutants (h); Q K is the blood perfusion of the kidney (L / h); C b is the concentration of organic pollutants in blood (ng / L); C K is the concentration of organic pollutants in the kidney (ng / L); P K:b is the kidney-blood partition coefficient of the organic pollutant, dimensionless;

[0040] Change rate of total organic pollutants in brain tissue (ng / h):

[0041]

[0042] Among them: A B is the amount of organic pollutants accumulated in brain tissue (ng); t is the accumulation time of organic pollutants (h); Q B is the blood perfusion of brain tissue (L / h); C b is the concentration of organic pollutants in blood (ng / L); C B is the concentration of organic pollutants in brain tissue (ng / L); P B:b is the brain tissue-blood partition coefficient of the organic pollutant, dimensionless;

[0043] Change rate of total organic pollutants in other tissues (ng / h):

[0044]

[0045] Among them: A R is the accumulation amount of organic pollutants in other tissues (ng); t is the accumulation time of organic pollutants (h); Q R is the blood perfusion of other tissues (L / h); C b is the concentration of organic pollutants in blood (ng / L); C R is the concentration of organic pollutants in other tissues (ng / L); P R:b is the other tissue-blood partition coefficient of the organic pollutant, dimensionless;

[0046] Changes in organic pollutant levels in blood (ng / h):

[0047]

[0048] Among them: A b It is the accumulation of organic pollutants in the blood (ng).

[0049] (4) Obtain and collect model parameters:

[0050] Physiological parameters of East Asian finless porpoises were obtained through dissection, and biochemical and toxicokinetic parameters of organic pollutants were collected from literature and databases. Physiological parameters included age, body length, body weight, liver volume, brain volume, kidney volume, fat volume, muscle volume, cardiac output, tissue blood flow, hepatic perfusion ratio, cerebral perfusion ratio, renal perfusion ratio, other tissue perfusion ratios, tissue-blood partition coefficient, liver lipid percentage, brain lipid percentage, kidney lipid percentage, fat lipid percentage, muscle lipid percentage, blood lipid percentage, liver water percentage, brain water percentage, kidney water percentage, fat water percentage, muscle water percentage, and blood water percentage. Biochemical and toxicokinetic parameters included the n-octanol-water partition coefficient, elimination half-life, target substance intake, hourly feeding volume, fish body concentration, assimilation efficiency, placental transfer coefficient, and breast milk partition coefficient.

[0051] Blood perfusion of each chamber (L / h):

[0052] Q t =Q C ×Q TC

[0053] Where: Q t Indicates the blood perfusion of liver, kidney, brain tissue or other tissues (L / h); Q C Indicates cardiac blood output, L / h; Q TC It represents the percentage of blood perfusion of the liver, kidney, brain tissue or other tissues, and is dimensionless.

[0054] Tissue-blood partition coefficient:

[0055]

[0056] Where: P t:b K is the partition coefficient of the pollutant between the liver, kidney, brain tissue or other tissues and blood, dimensionless; ow is the n-octanol-water partition coefficient of the pollutant, dimensionless; Fl t 、Fw t Fl is the lipid percentage and water percentage of the liver, kidney, brain tissue or other tissue compartments, dimensionless; b 、Fw b are the blood lipid percentage and water percentage, respectively, dimensionless.

[0057] In this example, the physiological parameters of the East Asian finless porpoise are shown in Table 1, and the biochemical parameters and toxicokinetic parameters are shown in Table 2.

[0058] Table 1. Physiological parameters of East Asian finless porpoises

[0059]

[0060]

[0061] Table 2. Biochemical and toxicokinetic parameters

[0062]

[0063] (5) Model solution and model verification:

[0064] The mass balance differential equations of each compartment were solved using R language (version 4.4.3), and the model prediction curves were drawn based on the solution results. The male and female model prediction curves were compared with the experimental data, that is, the organic pollutant content-time was fitted to test the model prediction effect. By adjusting the model parameters, the obtained organic pollutant content-time curve was made as close as possible to the experimental data. The male model prediction and verification results are shown in Figure 2. Figure 3 As shown in Figure 2, before adulthood (about 6 years old), the concentration of organic pollutants accumulated in the body of East Asian finless porpoises gradually increased with age. After adulthood, the accumulation of organic pollutants in the body gradually tended to a stable state over time. Figure 4 As shown, before adulthood (around 6 years old), the accumulation of organic pollutants in the East Asian finless porpoise gradually increases with age. After adulthood, due to the gestation and lactation cycles, the organic pollutants in the body show cyclical fluctuations. At a 95% confidence level, both male and female models have good prediction performance.

Claims

1. A method for constructing a physiological toxicokinetic model of organic pollutants in East Asian finless porpoises, characterized in that: The following steps are involved: Step (1) determining the kinetics of absorption, distribution, metabolism and excretion of organic pollutants in the East Asian finless porpoise, namely, ADME process; Step (2) determining the compartmental structure of the physiological toxicokinetics PBTK model based on the ADME process of the organic pollutants in the East Asian finless porpoise, including kidney, liver, brain tissue, and other tissues, wherein other tissues represent tissues and organs that are not set as independent compartments in the model structure; Step (3) establishing the differential equations describing the dynamic processes of organic pollutants in each compartment in the PBTK model; Step (4) obtaining and collecting model parameters; Step (5) solves the model to obtain the relationship between the accumulation of organic pollutants in each compartment and time.

2. The method for constructing a physiological toxicokinetic model of organic pollutants in East Asian finless porpoises according to claim 1, characterized in that: The differential equation in step (3) is as follows: Change rate of total organic pollutants in the liver: Among them: A L is the amount of organic pollutants accumulated in the liver; t is the accumulation time of organic pollutants; Q L is the blood perfusion of the liver; C b is the concentration of organic pollutants in blood; C L is the concentration of organic pollutants in the liver; P L:b is the liver-blood partition coefficient of the organic pollutant, dimensionless; ADI is the amount of organic pollutants that enter the liver after ingestion; RAM is the clearance rate of organic pollutants in the liver; The rate of change of total organic pollutants in the kidneys: Among them: A K is the amount of organic pollutants accumulated in the kidney; t is the accumulation time of organic pollutants; Q K is the blood perfusion of the kidney; C b is the concentration of organic pollutants in blood; C K is the concentration of organic pollutants in the kidney; P K:b is the kidney-blood partition coefficient of the organic pollutant, dimensionless; Change rate of total organic pollutants in brain tissue (ng / h): Among them: A B is the amount of organic pollutants accumulated in brain tissue; t is the accumulation time of organic pollutants; Q B C is the blood perfusion of brain tissue; b is the concentration of organic pollutants in blood; C B is the concentration of organic pollutants in brain tissue; P B:b is the brain tissue-blood partition coefficient of the organic pollutant, dimensionless; Change rate of total organic pollutants in other tissues: Among them: A R is the accumulation amount of organic pollutants in other tissues; t is the accumulation time of organic pollutants; Q R is the blood perfusion of other tissues; C b is the concentration of organic pollutants in blood; C R is the concentration of organic pollutants in other tissues; P R:b is the other tissue-blood partition coefficient of the organic pollutant, dimensionless; Changes in the levels of organic pollutants in the blood: Among them: A b It is the accumulation of organic pollutants in the blood.

3. The method for constructing a physiological toxicokinetic model of organic pollutants in East Asian finless porpoises according to claim 1, characterized in that: In step (4), physiological parameters of the East Asian finless porpoise are obtained by dissection, and biochemical parameters and toxicokinetic parameters of organic pollutants are collected from literature and databases; wherein the physiological parameters include age, body length, body weight, liver volume, brain volume, kidney volume, fat volume, muscle volume, cardiac output, tissue blood flow, liver blood perfusion ratio, brain blood perfusion ratio, kidney blood perfusion ratio, other tissue blood perfusion ratios, tissue-blood partition coefficient, liver lipid percentage, brain lipid percentage, kidney lipid percentage, fat lipid percentage, muscle lipid percentage, blood lipid percentage, liver water percentage, brain water percentage, kidney water percentage, fat water percentage, muscle water percentage, and blood water percentage; biochemical parameters and toxicokinetic parameters include n-octanol-water partition coefficient, elimination half-life, target substance intake, hourly food intake, fish body concentration, assimilation efficiency, placental transfer coefficient, and breast milk partition coefficient; Blood perfusion of each chamber: Q t =Q C ×Q TC Where: Q t Indicates the blood perfusion of the liver, kidney, brain tissue or other tissues; Q C Indicates cardiac blood output, L / h; Q TC It represents the blood perfusion percentage of liver, kidney, brain tissue or other tissues, dimensionless; Tissue-blood partition coefficient: Where: P t:b K is the partition coefficient of the pollutant between the liver, kidney, brain tissue or other tissues and blood, dimensionless; ow is the n-octanol-water partition coefficient of the pollutant, dimensionless; Fl t 、Fw t Fl is the lipid percentage and water percentage of the liver, kidney, brain tissue or other tissue compartments, dimensionless; b 、Fw b are the blood lipid percentage and water percentage, respectively, dimensionless.

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