Introduction
One of the fundamental aspects of mycotoxin exposure is their toxicokinetics. This term refers to the relationship between the concentration of a substance (in this case, the toxin) to which an individual is exposed and the concentration of toxicologically active compounds at the site of action (e.g., target organs such as the liver or kidneys) where the toxins exert their effect (Johanson, 2010).
Absorption
The term absorption refers to the process by which a chemical substance, after coming into contact with the organism, crosses biological barriers (such as the gastrointestinal tract) and enters the systemic circulation. At this level, the absorption rate (t máx) of the chemical from the site of application to the bloodstream (bioavailability, F) is established.
Distribution
The term distribution establishes the rate and intensity with which chemical substances are transported from the blood to the tissues. The apparent volume of distribution (Vd) indicates the toxin’s distribution in the body. It is calculated by dividing the total amount of toxin in the body by its plasma concentration.
Metabolism
Another fundamental process of toxicokinetics is metabolism. This process provides information about the speed and degree of chemical biotransformation into different types of metabolites.
Excretion
Finally, the term excretion indicates the elimination of the toxin from the organism. During the excretion process, the parameters of clearance (Cl: sum of all processes involved in the elimination of the toxin and its metabolites) and the elimination half-life (t½: time in which the plasma concentration of a drug is reduced by half) provide fundamental information.
Specified by the European Food Safety Authority (EFSA), the acronym ADME represents the four key processes that describe how toxins enter the organism, are metabolized, and are eliminated: absorption, distribution, metabolism, and excretion. These processes allow us to understand the biochemical alterations that occur, apply diagnostic tests, propose appropriate treatment in cases of intoxication, and study the development and use of products. ADME processes are a necessary tool for evaluating the efficacy of products developed for mitigation.
Aflatoxins
Absorption
Aflatoxins are highly absorbed in the gastrointestinal tract of poultry (90%). They stand out for their carcinogenic effect, which can affect any organ or system, especially the liver and kidney.
Distribution
The target organ of aflatoxins is the liver (Schrenk et al., 2020). Poultry with aflatoxicosis are drastically affected in the fatty acid composition at the hepatic level, increasing the level of lipid peroxidation, which leads to the generation of oxidative stress and the decrease of enzymatic and non-enzymatic antioxidants (Allah et al., 2018).
Metabolism
The biotransformation of aflatoxins takes place in the liver, kidney, and gastrointestinal tract. The biotransformation products of aflatoxin B1 (AFB1) are less toxic than the parent compound, with the exception of AFB1-8,9-epoxide (AFBO), which is obtained from cytochrome P450. Other metabolites are AFP1, AFM1, AFQ1, and aflatoxicol, which form glucuronide and sulfate conjugates. Among avian species, young animals and turkeys are the most sensitive to this group of mycotoxins (Coppock et al., 2018).
Excretion
Aflatoxins are eliminated via the urinary and fecal routes, with the latter being the result of both digestive and biliary excretion. It has been shown that the elimination of AFB1 from tissues is faster in adult animals than in young animals, and its plasma half-life is known to be 36.5 minutes (Hussain et al., 2010; Allah et al., 2018). Furthermore, these mycotoxins have been detected in eggs (Coppock et al., 2018).
Deoxynivalenol
Absorption
The absorption of deoxynivalenol (DON) in poultry is rapid, with a maximum time of 1 hour. However, its bioavailability has been reported to be low (5-20%) (Schrenk et al., 2023; Sun et al., 2022).
Distribution
In poultry, DON presents a wide distribution in many tissues (Schrenk et al., 2023). Its distribution is rapid and transient in tissues such as: muscle, abdominal fat, stomach, intestine, liver, kidneys, heart, brain, lung, skin, spleen, testicles, ovaries, and adrenal glands (Devreese et al., 2015).
Metabolism
Conjugation, sulfation, and deepoxidation processes represent the main metabolic routes for this mycotoxin, leading to metabolites with notably reduced toxicity. Extensive sulfation is observed in the liver and intestine, with DON-3-sulfate (DON-3S) being the predominant metabolite. Furthermore, efficient deepoxidation of DON to deepoxi-deoxynivalenol (DOM-1) is carried out in the intestine, which justifies the lower sensitivity of poultry to this mycotoxin, compared to other species. Other intestinal derivatives include the sulfonates DON-S1 and DON-S2 (Schwartz-Zimmermann et al., 2015).
Excretion
DON presents rapid elimination in poultry. Its metabolites are excreted mainly via the biliary and urinary routes, with a small amount of unmodified DON also being eliminated via the fecal route. Its plasma elimination half-life is less than 1 h (Schrenk et al., 2023).
Zearalenone
Absorption
Zearalenone (ZEN) is absorbed rapidly in broilers, laying hens, and turkeys. Generally, within a time interval that varies between 5 minutes and 2 hours (Liu et al., 2020). Some authors have pointed to low bioavailability in younger animals (Liu et al., 2020). Specifically, Devreese et al. (2015) observed a bioavailability of 6.87% to 10.2%.
Distribution
Its main metabolites, α-zearalenol (α-ZEL) and β-zearalenol (β-ZEL), can be identified in various tissues and body fluids, including blood, liver, kidney, muscle, intestine, and feces (Buranatragool et al., 2015). ZEN can be detected in the liver, kidney, and small intestine up to 1 hour after ingestion, while α-ZEL and β-ZEL remain detectable in those same organs for a maximum of 12 hours. Furthermore, both ZEN and its metabolites can be found in muscle up to 1 hour after exposure (Devreese et al., 2015).
Metabolism
In broilers, ZEN is rapidly transformed into α-ZEL and β-ZEL. Laying hens and broilers show a predominant biotransformation of ZEN to β-ZEL, while in turkeys, ZEN is preferentially converted to α-ZEL. For this reason, turkeys are more sensitive to this mycotoxin, as α-ZEL has higher estrogenic activity (Liu et al., 2020).
Excretion
In poultry, bile has been identified as an important excretion route for ZEN and its metabolites. Furthermore, in studies conducted on broilers, turkeys, and laying hens, the half-life of ZEN is estimated to be approximately 0.3 hours (Knutsen et al., 2017).
Ochratoxin A
Absorption
Ochratoxin A (OTA) is absorbed rapidly and in a high concentration in poultry. Thus, it can be detected in blood for a period of several hours. This process occurs mainly by passive diffusion, particularly in the proximal region of the jejunum, after exposure through the stomach. In chickens, bioavailability is estimated to reach 40% (Schrenk et al., 2020).
In a study by Devreese et al. (2018), OTA absorption was observed to be rapid, with a maximum time between 0.31 and 1.88 h in laying hens, turkeys, and ducks. In broilers, this maximum time extends to 1.43–4.63 h.
Distribution
OTA is distributed in all organs, but is most prevalent in the kidney, liver, and muscle (Schrenk et al., 2020).
Metabolism
Regarding its metabolism, the major metabolite of OTA is OT-alpha (OTa), generated by the intestinal microbiota in monogastrics. OTa is partially absorbed in the intestine, but does not accumulate in the kidney; instead, it is rapidly excreted via urine in the form of a glucuronide. The predominant metabolic pathway involves the hydrolysis of OTa followed by its conjugation with glucuronic acid, with oxidative metabolism being of less relevance (Schrenk et al., 2020).
Excretion
OTA is eliminated and excreted slowly due to its strong binding to plasma proteins, which limits its metabolism. On the other hand, a process of renal tubular reabsorption of OTA that has been previously secreted or filtered has been described, which favors its accumulation in renal tissue, delays its excretion, and can contribute to its toxicity (Schrenk et al., 2020).
In poultry, the elimination of OTA is faster compared to other species, resulting in less accumulation of the toxin. Likewise, it has been observed that OTA can be transferred to the egg when its concentration in the feed is high, for example, at levels of 10 mg/kg live weight (Schiavone et al., 2008; Battacone et al., 2010). Finally, the elimination half-life of OTA has been reported to be approximately 3.3 hours (Ruprich et al., 1991).
T-2 toxin
Absorption
T-2 toxin (T-2), like other trichothecenes, is rapidly absorbed in the intestinal tract of poultry, undergoing metabolization and elimination of 80-90% within 48 h (Sokolović et al., 2008). Broekaert et al. (2015) reported 10.6% absorption in broilers after administration of 0.5 mg/kg live weight. Maximum T-2 absorption is observed 15-90 minutes after consuming contaminated feed (Reddy et al., 2004).
Distribution
T-2 toxin is distributed widely and rapidly, as in other species. In one study, maximum concentrations of T-2 toxin and its metabolites were observed at 3 h in the liver and kidneys and at 4-6 h in muscle (Chi et al., 1978).
Metabolism
T-2 toxin is generally metabolized and eliminated after ingestion, into more than 20 metabolites, HT-2 being the main one. The main metabolic reactions are: hydrolysis, hydroxylation, deepoxidation, and conjugation (CONTAM, 2011).
Excretion
This mycotoxin is eliminated rapidly, more than 50% in 24 hours, and mainly via the fecal route (CONTAM, 2011).
Fumonisins
Absorption
In the case of fumonisins, their absorption in poultry is 2-3%, so the gastrointestinal tract is considered one of the target organs of this mycotoxin (Knutsen et al., 2018). Although absorption is rapid, it is limited to 20 minutes after feed administration (Knutsen et al., 2018). Turkeys and ducks are more sensitive to these mycotoxins than laying and breeding hens.
Distribution
It is distributed rapidly in the tissues and is found mainly in the liver, kidney, and muscle (Knutsen et al., 2018).
Metabolism
The metabolism of fumonisins includes hydrolysis reactions, with hydrolyzed forms, such as hydroxy-fumonisin B1 (HFB1); and partially hydrolyzed forms, such as phosphorylated fumonisin B1 (PFB1). In addition to acylation and transamination in the liver (Hartinger et al., 2011). Given the high structural similarity with sphingolipids, the imbalance in the sphinganine/sphingosine ratio (Sa/So) is considered a biomarker of great interest for determining the toxicity of fumonisins (Guerre et al., 2022).
Excretion
A large part of the fumonisins is excreted via the biliary route without biotransformation, up to 90% of the exposure dose. Both fumonisins and their metabolites have been detected in the feces, and these mycotoxins are known to have a half-life of less than 4 hours (Knutsen et al., 2018).
Emerging mycotoxins
Emerging mycotoxins are a chemically diverse group of mycotoxins that are not routinely determined, and for which there is no regulation or legislative recommendation (Krska et al., 2015).
Enniatins and Beauvericin
Absorption
In poultry, emerging mycotoxins show low absorption, unlike other species, with a bioavailability (F) of 5% and 11% for enniatin B1 and B, respectively.
Distribution
Enniatins present high distribution in tissues in broilers. Studies have reported that the volume of distribution in these animals is 25 L/kg (Fraeyman et al., 2016).
Metabolism
The metabolism of these mycotoxins includes hydroxylation and carboxylation reactions (Ivanova et al., 2011).
Excretion
These mycotoxins are eliminated by ABC transporter proteins (P-gp, MRP 2, BCRP) directly into the intestinal lumen. High elimination has been described in chickens compared to other species. Considering the low bioavailability and high elimination of enniatins in poultry, the toxicity caused by these mycotoxins in these animals is very low.
| MYCOTOXINS | ADME processes | |||
|---|---|---|---|---|
| Absorption | Distribution | Metabolism | Excretion | |
| Aflatoxins | · Rapid absorption in the gastrointestinal tract (90%; GIT) · Young poultry are more sensitive to this toxin than adults | · Liver is the main distribution organ | · Liver, kidney, and intestinal tract · AFB1-8,9-epoxide (the most toxic metabolite obtained through cytochrome P450) · Metabolites: AFP1, AFM1, AFQ1, and aflatoxicol | · Urinary and biliary tracts · Elimination rate: adults > young people · t1/2: 36.5 minutes · Transfer to eggs |
| DON | · Rapid absorption (<1 hour) and low bioavailability (5–20%)
| · Rapid and transient distribution · It is distributed to most major tissues, including the brain, causing inflammation | · Phase II (sulphation): DON-3S in the liver · Intestine: DON-S1, 2 and 3 · Biotransformation (deepoxidation): DOM-1 and 3 | · Biliary and urinary tract: DON metabolites (biomarkers) · t1/2: < 1 hour
|
| ZEN | · Rapid absorption (<1 hour) in the gastrointestinal tract · Bioavailability: young people < adults (F ≈ 6–10%)
| · In the liver, kidney, and intestine, ZEN is detected up to 1 hour after oral administration. · The metabolites are widely distributed (small intestine > liver > kidney and muscle). α-ZEL and β-ZEL are detectable for up to 12 hours | · Biotransformation catalysed by 3α- and 3β-hydroxysteroid dehydrogenases (HSDs) in plasma · Laying hens and chickens: ↑ β-ZEL · Turkeys: ↑ α-ZEL · Oestrogenic activity: α-ZEL > β-ZEL, turkeys more sensitive
| · Biliary tract (ZEN and metabolites) · t1/2: 0.3 hours
|
| OTA | · Rapid absorption (0.31–1.88 hours; in broiler chickens 1.43–4.63 hours) · Passive diffusion in the proximal region of the jejunum after exposure through the stomach · Bioavailability = 40% | · High affinity for plasma proteins (albumin) → long half-life · Distribution in all tissues, especially kidney, liver and muscle
| · Gut microbiota: OTα · Hydrolysis of OTα + conjugation with glucuronic acid · Oxidative metabolism | · Urinary tract · Faeces · Reabsorption in renal tubules (accumulation in renal tissue) · Rapid elimination · t1/2: 3.3 hours · Transfer to eggs |
| T-2 | · Rapid absorption in the gastrointestinal tract · Broiler chickens: 10% absorption · T max: 15–90 minutes | · Rapid and extensive distribution · Liver, kidneys and skin barrier | · Hydrolysis: main metabolite HT-2 · Hydroxylation · Deoxidation · Conjugation | · Rapid elimination (>50% in 24 hours) · Faeces
|
| Fumonisins | · Rapid but low absorption, limited to 20 minutes · Bioavailability < 4% · Laying hens: F = 0.7% · Turkeys: F = 3% · Ducks: F = 2% | · Rapid tissue distribution · Liver, kidneys, and muscle
| · Biomarker: Sa/So ratio · Hydrolysis (HFB1 and PFB1) · Acylation · Transamination | · Rapid elimination · Biliary route without biotransformation · Faeces > urine · t1/2< 4 h |
| ENN, BEA | · Low absorption compared to other species · Bioavailability 5 and 11% (ENN B1 and ENN B respectively) | · High distribution of ENN B1 compared to other species · Apparent volume of distribution (Vd) = 25 L/kg in broiler chickens | · Hydroxylation · Carboxylation | · ABC transporter proteins (P-gp, MRP 2, BCRP): intestinal lumen |
Table 1. Toxicokinetics of common and emerging mycotoxins in poultry.
Conclusion
The study of the processes involved in toxicokinetics is essential to understand how mycotoxins affect the different species used in animal production. Mycotoxins are capable of generating significant health problems in poultry, as well as significant economic losses for the global poultry industry. For this reason, it is crucial to recognize the relevance of these toxic substances and act accordingly, implementing effective strategies.
