Received: 24/05/2025 Accepted: 06/10/2025 Published: 29/10/2025 1 of 7
https://doi.org/10.52973/rcfcv-e353706 RevistaCientíca,FCV-LUZ/Vol.XXXV
ABSTRACT
The present study aims to describe the metabolism of the lead in
sheep (Ovis aries) by implementing a toxicokinetic approach and
to determine the bioavailability. A clinically healthy, one–year–old,
non–lactating ewe (40 kg) received a single intravenous dose of
lead acetate (0.165 mg Pb·kg
-1
) followed by oral administration
(2.5 mg Pb·kg
-1
) after a 40 day washout. Lead, zinc, copper and
calcium levels in the diet were measured before feeding. Serial
blood samples were collected over 5 hours (h) (intravenous)
and 9 h (oral) and analyzed by electrothermal atomic absorption
spectrophotometry. Concentration–time data were tted to a
two compartment model (bicompartmental biexponential for
intravenous; biexponential with absorption term for oral) to
derive distribution and elimination halflives, clearance, volumes
of distribution, mean residence time, area under the curve, and
absolute bioavailability. Analysis of ewe feed revealed excessive
calcium intake. Following intravenous dosing, lead peaked at
870µg·L
-1
, with a rapid distribution (T
½
α = 0.004 h) and slow
elimination (T
½
β = 6.4 h). Oral administration yielded a lower
peak (522 µg·L
-1
) with absolute bioavailability of only 2% (High
dietary calcium likely suppressed gastrointestinal absorption),
while steady–state volume of distribution (0.275 L·kg
-1
)
indicated extensive tissue accumulation. The ndings highlight
compartmental modelling as a critical tool for assessing lead
toxicokinetic in ruminants.
Key words: Lead; ewe; toxicokinetics; compartment analysis;
bioavailability
RESUMEN
El propósito de este estudio es describir el metabolismo del plomo
en ovejas (Ovis aries) con un enfoque toxicocinético y determinar
su biodisponibilidad. Se utilizó una oveja clínicamente sana de un
año de edad y no lactante (40 kg) quien recibió una dosis única
de acetato de plomo intravenosa (0,165 mg Pb·kg
-1
), seguida de
una administración oral (2,5 mg Pb·kg
-1
) después de un periodo
de depuración de 40 días. En el presente estudio, se midieron los
niveles de plomo, zinc, cobre y calcio presentes en la dieta antes
de su administración. Se colectaron muestras sanguíneas en serie
durante un período de cinco horas (intravenosa) y nueve horas (oral)
y se analizaron mediante espectrofotometría de absorción atómica
electrotérmica. Tambien se ajustaron los datos de concentración–
tiempo a un modelo bicompartimental (bi–exponencial para
intravenosa; bi–exponencial con término de absorción para oral)
para calcular las vida mediade distribución y eliminación, el
aclaramiento, los volúmenes de distribución, el tiempo medio de
residencia, el área bajo la curva y la biodisponibilidad absoluta.
El análisis del alimento mostró un exceso de calcio dietético.
Tras la administración intravenosa, la concentración máxima de
plomo alcanzó un pico de 870 μg·L
-1
, una distribución rápida (T
½
α
= 0,004h) y una eliminación lenta (T
½
β = 6,4 h). La administración
oral del compuesto resultó en un pico signicativamente más
bajo (522 μg·L
-1
) con una biodisponibilidad absoluta de 2%
probablemente atribuido a la interferencia del calcio dietético
en el proceso de absorción gastrointestinal del compuesto. El
volumen de distribución en estado estacionario (0,275 L·kg
-1
)
indicó una acumulación tisular extensa. Los resultados ponen de
maniesto la relevancia del modelado compartimental como una
herramienta fundamental para la evaluación de la toxicocinética
del plomo en rumiantes.
Palabras clave: Plomo; oveja; toxicocinética; análisis
compartimental; biodisponibilidad
Lead toxicokinetics following intravenous and oral administration in
non–lactating ewe: A preliminary study
Toxicocinética del plomo tras administración intravenosa y
oral en ovejas no lactantes: Un estudio preliminar
Boufedda Nadia , Sellaoui Sassia* , Arab Hadda , Boudaoud Amine , Mehennaoui Smail
University of Batna 1, Institute of Veterinary and Agricultural Sciences, Veterinary Department, Research laboratory environment, production, and
animal health (LESPA). Batna 05000, Algeria. *Corresponding author: sacia.sellaoui@univ–batna.dz
Lead toxicokinetics in non-lactating ewe: A preliminary study / Nadia et al.______________________________________________________
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INTRODUCTION
Lead (Pb) is the most persistent ubiquitous, highly toxic heavy
metal with no known biological role. Due to its non–biodegradable
nature and widespread use, it accumulates in the environment
with increasing hazards. Ruminants are highly susceptible to Pb
toxicity and its wide range of adverse effects [1, 2, 3]. Due to their
non–discriminatory eating habits, cattle (Bos taurus) are more
frequently affected compared to other species [4].
This toxicity manifests as nervous and digestive symptoms,
including anorexia, blindness, convulsions, and opisthotonos.
Additionally, cattle often suffer from subclinical Pb poisoning due to
grazing on Pb–contaminated pastures [5, 6, 7, 8]. Sheep (Ovis aries)
living in contaminated areas are no less sensitive to Pb toxicity [3, 9,
10, 11]. The primary indicators of chronic Pb exposure in ruminants
include blood Pb levels [8, 11, 12], zinc protoporphyrin [13], and
δ–aminolevulinic acid dehydratase (δ–ALAD) inhibition [14] all of
which reflect the presence of metabolically active Pb in the body.
Unlike in humans, where several studies have permitted
to propose some pharmacokinetic models allowing a better
characterization of the Pb disposition in the human’s organism [15,
16, 17], in ruminants’ studies are still lacking, and many aspects
need further clarication.
Among the few studies conducted on the subject, one notable
example is the work by Milhaud and Mehennaoui [13] who applied
a two–compartment pharmacokinetic model to monitor blood Pb
levels in cattle during a chronic Pb exposure. To study the transfer
of Pb into milk, muscle and offals in the lactating ewes, Mehannaoui
et al. [18] employed a toxicokinetic approach and Waldner et al.
[19] used a single–component exponential model to describe
the changes in blood lead levels over time in exposed cattle after
ingestion of abandoned batteries.
Given that understanding the metabolic balance of a metal is
more effectively achieved through a kinetic approach than by simply
measuring the amounts ingested and excreted in urine and feces
[20] and considering the limited research on Pb toxicokinetics in
ruminants, a preliminary study was carried out to investigate the
disposition of Pb in sheep following different routes of exposure. A
single dose of Pb acetate was administered intravenously (IV) and
orally. Toxicokinetic parameters were determined for each of the two
routes of administration with a focus on the absolute bioavailability
of Pb. The absolute bioavailability of Pb refers to the fraction of
Pb that reaches the systemic circulation after oral ingestion and
absorption from the gut [11, 20, 21]. The study aimed at describing
Pb fate within the body in sheep using a toxicokinetic approach.
MATERIALS AND METHODS
This work was conducted at the sheepfold of the Veterinary
Department at the University of Batna 1, after approbation of the
experimental protocol by the Scientic Committee of the Institute
of Veterinary and Agricultural Sciences.
For the experiment, a clinically healthy, non–lactating one–year–
old ewe (40 kg), was recruited. Body weight was measured using
a mechanical scale designed for sheep and calves (PATURA KG;
Ref. 430350; Germany). Before and during the experiment, water,
commercial feed and dry litter were available. The levels of Pb,
zinc (Zn), copper (Cu), and calcium (Ca) were measured in the feed
before it was fed to the ewe. Animal welfare and access to veterinary
care have been insured throughout the period of the experiment.
Experimental design
The ewe received a single IV bolus administration of Pb acetate
at a dose of 0.165 mg Pb·kg
-1
body weight. The total dose
administered (6.6 mg) was diluted in 2 mL of sterile water for
injection to achieve a concentration of 3.3 mg Pb·mL
-1
. Blood
samples (4 mL) were collected from the left jugular vein into
heparinized tubes under vacuum, which is known not to interfere
with the analysis of trace elements, metals or metalloids. Sampling
was performed at successive time points: 2, 5, 10, 15, 30 min and
1 hour (h), 1h 30 min, 2 h, 3 h, 4 h, 5h after dosing.
Additionally, after a 40 day (d) washout period, the ewe received
a single oral administration of Pb acetate at a dose of 2.5 mgPb·kg
-1
of body weight. Pb was encapsulated in a gelatin capsule and placed
over the base of the tongue to ensure that the animal swallowed
the capsule. Serial blood sampling was performed at different
consecutive time points: 0, 0.25, 0.5, 1, 1.5, 2.5, 4, 5, 6 and 9 h.
Chemical analysis
Determination of blood Pb concentrations
A volume of 1 mL of blood was transferred to a teflon bottle and
5 mL of HNO
3
was added. The sample was left at room temperature
for at least 30 min. The teflon bottle without its lid, was placed on
a sand bath (Combiplac – Sand; J.P.Selecta; Spain) and heated at
150°C for one hour until the acid volume was reduced to 1mL.
Subsequently, 2 mL of HNO
3
and 1 mL of concentrated HCl were
added to the sample. The bottle was sealed and heated on a sand
bath at 150°C for one h. The digested sample was then transferred
to a 50 mL vial, ltered and made up to nal volume with distilled
water. Pb concentrations in whole blood were measured by
electrothermal atomic absorption spectrophotometry (Analyst
100; PerkinElmer; USA). The operating conditions were drying
at 200°C, ashing at 700°C and atomizing at 1800°C. All samples
were analyzed in duplicate. The linearity of the calibration curve
extended to 50 µg·L
-1
. The detection limit was estimated at 4 µg·L
-1
.
Determination of feed trace element concentrations
Hay and granulated feed samples were collected from the ewe’s
diet to assess the intake of trace elements. The feed samples
were subjected to a wet digestion using two pure acids, HNO
3
and
HCLO
4
[22]. First, 5 mL of HNO
3
(15N) was added to 1 g of sample
and boiled on a sand bath for 30 min. Then, 3 mL of 70% HClO
4
was added, and the mixture was boiled until the acidic volume
was reduced to 1 mL. After cooling to ambient temperature, 10
mL of deionized water was added and ltered through a Watmann
lter (N 540) in a volumetric flask and adjusted to the nal volume
of 50mL. Pb and Cd concentrations were determined by using
graphite furnace atomic absorption spectrometry (Analyst 100;
PerkinElmer; USA), while Ca, Zn, Fe and Cu were measured by flame
atomic absorption spectrometry (Shimadzu AA-6800; Japan).
Lead toxicokinetics in non-lactating ewe: A preliminary study / Nadia et al.______________________________________________________
_________________________________________________________________________________________________Revista Cientica, FCV-LUZ / Vol.XXXV
3 of 7
Toxicokinetics analysis
Blood Pb concentrations following IV and oral administrations
were subjected to compartmental analysis, non–linear least square
regression, using a program adapted from PK Solver software [23].
A biexponential equation, representing a bicompartimental model
with elimination occurring from the central compartment, was tted
to the blood Pb concentrations for IV and oral administrations:
For IV administration:
○ C(t) = Ae
-αt
+ Be
-βt
For oral administration:
○ C(t) = Ae
-αt
+ Be
-βt
- Ce
-Kat
Where: C(t) is the blood concentrations at time t, α and β are the
exponential terms, A is the blood lead concentration at time t=0
during the distribution phase, B is the blood lead concentration at time
t=0 during the elimination phase and Ka is the absorption constant.
The area under the blood lead concentration curve (AUC) can either
be calculated by the trapezoidal method or estimated as follows:
The half–life (T
½
α) was determined during the distribution phase
using the following equation:
The half–life (T
1/2
β) was determined during the elimination phase
as below:
The total body clearance (Cl) was calculated as following:
Following IV bolus administration of a compound, two distinct
volumes of distribution can be determined [24].
» The volume of distribution of the central compartment Vc:
where C
0
is the concentration at t=0
» The volume of distribution at steady state V
ss
:
V
ss
= Cl × MRT
(IV)
The Mean Residence Time (MRT) after IV administration was
calculated as follows:
Where AUMC
0-∞
is the area under the moment curve and AUC
0-∞
is the area under the blood concentration curve. In addition, the
ratio of the area under the moment curve to the area under the
concentration–time curve (AUMC/AUC), commonly used as a
denition for the MRT of drug molecules in the body should rather
be considered as a method of evaluating this parameter.
The Absolute bioavailability F is the fraction absorbed via gastro–
intestinal route and was calculated as follows:
RESULTS AND DISCUSSION
The bioavailability of Pb has been assessed in mice (Mus musculus),
monkeys (Platyrrhini sp.), rabbits (Oryctolagus cuniculus), rats (Rattus
norvegicus), and swine (Sus scofa domesticus) [25, 26, 27] but to our
knowledge, no IV Pb dosing data have existed for ruminants prior to
this study. This is the rst investigation to administer Pb intravenously
in ewes, providing novel insights into Pb toxicokinetics in sheep using
both IV and oral administration of Pb acetate.
The use of a non–lactating ewe allowed us to avoid potential
confounding factors related to lactation on Pb kinetics [19, 28, 29].
Similarly, the oral dose of 2.5 mg·kg
-1
was selected to prevent clinical
toxicity while ensuring measurable blood Pb levels for kinetic analysis.
No clinical signs of Pb intoxication were observed throughout the
study, conrming the safety of the selected dose for toxicokinetic
purposes. According to Rodrigues–Estival et al. [14], sheep show
clinical poisoning at blood Pb ≈350 µg·L
-1
, while Mehennaoui etal.
[5] attest that this requires more than twice this concentration
(750g·L
-1
), and Sellaoui et al. [12] observed anemia at 445 µg·L
-1
after chronic dosing. In this study, postdosing levels far exceeded
these thresholds without any signs of toxicity. The bioavailability of
heavy metals depends largely on their oxidation state and solubility
[29, 30]. Regarding the chemical species of the lead, the Pb acetate
we used is a reference soluble compound that is expected to fully
dissolve in gastrointestinal fluids upon ingestion [31].
Dietary intakes of Cd and Pb proved negligible, as both metals
remained below detection limits in the food analysis, thus contributing
minimally to systemic Pb levels (TABLEI). Consequently, blood Pb
concentrations remained below the detectable threshold until IV
dosing. Immediately after IV administration, blood Pb levels rose
immediately to a pic of 870 µg·L
-1
(FIG. 1), followed by rapid decline
between 10–30 min (distribution phase) and slower elimination
thereafter. Concentrations measured 317 µg·L
-1
at 5 h post–dosing,
demonstrating prolonged circulation despite initial distribution kinetics
TABLE I
Mineral and heavy metal composition of the diet
and estimated daily intake in the Ewe
Parameters
Rations
Hay Maize Barely Feed intake·day
-1
Cu (mg·kg
-1
) 7.8 8 8.4 mg
Zn(mg·kg
-1
) 15 24 19.5 24 mg
Ca (g·kg
-1
) 22 4.7 5.7 24 g
Fe(g·kg
-1
) 106.5 70 87 141.9 g
Cd (µg·kg
-1
) <DL <DL <DL <DL
Pb (µg·kg
-1
) <DL <DL <DL <DL
DL:DetectionLimit
Lead toxicokinetics in non-lactating ewe: A preliminary study / Nadia et al.______________________________________________________
4 of 7 5 of 7
FIGURE 2 illustrates the time course of Pb concentrations
following oral administration. Blood Pb levels started to increase
from the initial 15 min, reaching a maximum of 522 µg·L
-1
(predicted
value) after 0.54 h. Then the blood Pb concentration initiated a fast
decay following a biexponential model. The Pb level in the blood
was only 56 µg·L
-1
6 hours after oral administration.
deciency increases systemic Pb bioavailability by enhancing
intestinal absorption and decreasing fecal excretion [11, 21, 35].
Together, these ruminal and dietary mechanisms likely explain
the low bioavailability observed in this study. As a result, most of
the ingested Pb remains unabsorbed and is eliminated via feces
[10, 36]. Overall, ruminants show greater tolerance to Pb compared
to monogastrics, whose acidic stomach environment increases
metal solubility and absorption [37]. The ruminal microbial
conversion of soluble Pb to insoluble sulde is a key physiological
mechanism limiting Pb bioavailability in ruminants, although the
full adaptation mechanisms to chronic exposure remain unclear.
Pb bioavailability in this study (2%) was lower than approximately
4% reported in lambs [36, 38], consistent with age–related
differences in Pb absorption, with younger individuals absorbing
substantially more Pb than adults [39] despite their ability to avoid
Pb–contaminated forage as adults. Indeed, lambs have an: i)
immature rumen, which limits the microbial conversion of soluble
Pb into insoluble sulde [10]; ii) increased intestinal permeability
and higher expression of metal transporters (DMT1) [30]; iii)
elevated calcium requirements that enhance Pb–Ca competition
at the intestinal level [11]; and iv) slower renal clearance, which
prolongs systemic exposure [38, 39].
Following IV administration, blood Pb concentrations exhibited
a biexponential decline. The same pattern was observed after
oral administration, notably during the decay of the blood Pb
phase. This biexponential model aligns with previous studies on
Pb disposition in cattle, sheep [5, 18, 30, 40], and humans [15,
16, 17], where blood Pb levels after long–term exposure, reflect
equilibrium with tissue stores, especially bone. However, a single
oral dose in this study did not achieve steady–state blood Pb
levels seen in chronic exposure, indicating shorter distribution
and elimination phases in single–dose kinetics.
The toxicokinetic parameters for both routes of administration
are listed in TABLE II.
Clearance (Cl) values differed markedly between routes: 1.4 L·h
-1
for IV and 0.12 L·h
-1
for oral administration. The higher clearance
following IV dosing suggests efficient systemic elimination,
predominantly via renal pathways, consistent with the kidney’s
role as a primary organ for Pb excretion [35]. The lower clearance
observed after oral administration likely results from limited
bioavailability and rst–pass effects.
The two–compartment model parameters revealed an extremely
short distribution half–life (T
1/2
α) after IV administration (0.004 h),
indicating rapid equilibration between blood and peripheral tissues.
Oral administration showed a longer distribution half–life (0.3 h),
consistent with slower systemic uptake. The elimination half–
life (T
1/2
β) was 6.4 h post–IV and 2 h post–oral,reflecting slower
clearance after IV dosing, possibly due to tissue sequestration and
delayed release.These ndings contrast with longer elimination
half–lives reported in lactating cows after IV Pb acetate [41],
suggesting species and physiological status differences.
The absorption half–life (T
1/2
Ka) after oral administration was
0.13 h, indicating rapid gastrointestinal absorption of the fraction of
Pb that is bioavailable, despite the overall low systemic availability
The oral bioavailability of Pb acetate was approximately 2%,
consistent with previous reports in ruminants [32], despite
differences in the chemical form of Pb and measurement
methodologies. This limited absorption can be attributed
to multiple physiological and dietary factors. First, rumen
microorganisms convert soluble Pb salts into insoluble Pb sulde,
thereby reducing the fraction of absorbable Pb²
+
[33]. Second,
the ewe in this study received a diet particularly rich in calcium
(24 g instead of 15 g required by the highest–producing lactating
ewe), a well–documented inhibitor of Pb absorption due to its
competition for intestinal transporters [17]. High dietary Cahas
been shown to signicantly reduce Pb uptake [34], whereas Ca
FIGURE 1. Lead blood concentrations in ewe after a single IV administration of
0.25 mg Pb·kg
-1
body weight
FIGURE 2. Lead blood concentrations in ewe after a single oral administration
of 2.5 mg Pb·kg
-1
body weight
Lead toxicokinetics in non-lactating ewe: A preliminary study / Nadia et al.______________________________________________________
_________________________________________________________________________________________________Revista Cientica, FCV-LUZ / Vol.XXXV
5 of 7
(F = 2%). This low bioavailability is corroborated by the area under
the concentration–time curve (AUC
0–∞
), which was markedly lower
after oral administration (1,709 µg·h
-1
·L
-1
vs 5,342 µg·h
-1
·L
-1
IV),
conrming minimal systemic uptake. According to Phillips et al.
[36] and Kumar et al. [27], inorganic Pb is not typically absorbed
by rumen microorganisms and is effectively excluded from cells.
MRT values were consistent with these observations: 7.7 h after
IV administration and 3 h after oral dosing, indicating prolonged
systemic exposure when lead bypasses gastrointestinal barriers.
The multiphasic elimination pattern observed, with distinct
distribution and elimination phases, supports the involvement of
multiple compartments exhibiting different retention and release
kinetics [29, 35, 40]. Lead’s afnity for soft tissues and bone likely
contributes to this kinetic complexity, as these compartments
serve as reservoirs that slowly release lead back into circulation.
CONCLUSION
This study provides the first comprehensive assessment
of intravenous Pb toxicokinetic in ewes, offering valuable
reference data for ruminants. The results conrmed a very low
oral bioavailability of Pb acetate (2%) in adult non–lactating
ewes, attributed to physiological mechanisms such as ruminal
microbial conversion and high dietary calcium intake, both of
which signicantly limit intestinal absorption.
The biexponential kinetic proles observed after both IV and
oral administration indicate multiphasic disposition with limited
tissue distribution and prolonged systemic persistence. The higher
systemic clearance and longer elimination half–life after IV dosing
reflect tissue sequestration and slow redistribution, underscoring
the complexity of Pbkinetics in ruminants. These ndings highlight
species–specic differences in Pb disposition and the influence
of age, diet, and administration route. Future studies should
explore chronic exposure scenarios, the role of bone as a long–
term reservoir, and the modulation of bioavailability under varying
dietary and physiological conditions to better assess health risks
and guide regulatory thresholds in livestock.
Conflict of interest
There is no conflict of interest between the authors.
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TABLE II
Toxicokinetic parameters describing lead disposition
in ewe after IV and oral administrations
Parameters Units
IV
administration
Oral
administration
A
µg·L-1 153716 1×10
-6
α
h 180 2.3
B
µg·L-1 487 685
β
h 0.11 0.37
T
1/2
α
h 0.004 0.3
T
1/2
β
h 6.4 2
T
1/2
Ka
h – 0.13
V
L·kg
-1
0.05 0.32
Cl
L·h
-1
1.4 0.12
AUC
0-∞
µg·L-1·h
-1
5342 1709
AUMC
µg·L-1·h
2
41356 4905
MRT
h 7.7 3
V
ss
L 11 –
F
% – 2
Note: A and Bareconcentrationsatt=0duringdistributionandeliminationphases
respectively.T
1/2
α:distributionhalf–life,T
1/2
β:eliminationhalf–life,T
1/2
Ka: constant
ofabsorptionhalf–life,V:centralcompartmentvolume,V
ss
:steady–statevolume
ofdistribution,Cl:totalbloodclearance,AUC:AreaUndertheCurve,AUMC: Area
UndertheMomentCurve,MRT:meanresidencetime,F:absolutebioavailability.
Pharmacokineticparametersshowedavolumeofdistributionatsteadystate(V
ss
)
of0.275L·kg
-1
,indicatinglimitedtissueaccumulation.Interestingly,theapparent
volumeofdistribution(V)washigherafteroral(0.32L·kg
-1
)thanIVadministration
(0.05L·kg
-1
),likelyduetodierencesinabsorptionandearlydistribution
Lead toxicokinetics in non-lactating ewe: A preliminary study / Nadia et al.______________________________________________________
6 of 7 7 of 7
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heavy metal contaminated shooting ranges. Sci. Total Environ.
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