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Literature

Pig
14C-estradiol
Infusion into
selected
portions of
the gastro-
intestinal
tract of gilts.
Blood samples were
collected from the jugular
and portal veins.
The concentration
of free estrogens in
the jugular vein was low
(< 1%) The concentration
of conjugated estrogens in
the jugular vein peaked
rapidly after instillation.
60-90% of the radiolabel
in blood was present as
glucuronide conjugates;
smaller amounts of
sulfated compounds were
detected and approximately
1% as diconjugates. The
principal steroid identified
after cleavage by
ß-glucuronidase and
sulfatase was estrone.
Conjugation occurs as
estradiol crosses the mucosa
of the gastrointestinal tract,
and free estradiol in the
ortal plasma is conjugated
during the first pass through
the liver.
Moore et al., 1982. J. Anim. Sci.,
55, 124-134 as cited by
Toxicological Evaluation of certain
Veterinary Drug Residues in Food.
WHO Food Additives Series: 43,
prepared by the Fifty-second meeting
of the Joint FAO/WHO Expert
Committee on Food Additives
(JECFA), 2000.
Pig
17ß-Estradiol-
D-glucuronide
Instillation into
sections of
intestineof
gilts.
Blood samples were
collected from the jugular
and portal veins.
The limiting factor in
absorption of conjugates
was hydrolysis to free
estrogen.
Pohland et al., 1982 J. Anim. Sci.,
55, 145-152as cited by Toxicological
Evaluation of certain Veterinary
Drug Residues in Food. WHO Food
Additives Series: 43, prepared by the
Fifty-second meeting of the Joint
FAO/WHO Expert Committee on
Food Additives (JECFA), 2000.
Pig
Gestadiol-17ß-
D-glucuronide
Gavage
A possible dose-limiting rate
of absorption was observed at
the highest dose (4 mmol 3H-
estradiol glucuronide)
Coppoc et al., 1982,J. Anim. Sci.,
55, 135-144 as cited by Toxicological
Evaluation of certain Veterinary
Drug Residues in Food. WHO Food
Additives Series: 43, prepared by the
Fifty-second meeting of the Joint
FAO/WHO Expert Committee on
Food Additives (JECFA), 2000.
Pig
Crystalline estradiol
(10 mg in cocoa butter)
Gavage
The concentrations of estradiol,
estrone, estradiol glucuronide,
and estrone sulfate in the hepatic
portal vein rose within 5 min and
remained elevated for several
hours. Estrogens administered
orally are conjugated by the gut
wall and pass to the liver, where
they enter either the bile pool for
enterohepatic circulation or the
bloodstream.
Ruoff & Dziuk, 1994. Domest.
Anim. Endocrinol., 11, 197-208
as cited by Toxicological Evaluation
of certain Veterinary Drug Residues
in Food. WHO Food Additives Series:
43, prepared by the Fifty-second
meeting of the Joint FAO/WHO
Expert Committee on Food
Additives (JECFA), 2000.
Wister Rat,
female
17ß-Estradiol
Intravenous
administration
of 0.1 mg/kg bw
 
Gavage of
10 mg/kg bw
Concentrations of estradiol in
liver was 20 times higher after
intragastric than after intravenous
administration. Absolute bio-
availability was 8.3% after an
intragastric dose of 10 mg/kg bw.
The total clearance was
154 ml/min per kg bw. The half-life
of estradiol in liver was 2.6 h
Schleicher et al., 1998. Pharmacol.
Toxicol., 82, 34-39 as cited by
Toxicological Evaluation of certain
Veterinary Drug Residues in Food.
WHO Food Additives Series: 43,
prepared by the Fifty-second
meeting of the Joint FAO/WHO
Expert Committee on Food
Additives (JECFA), 2000
Rat, female
Levonorgestrel
and
17ß-Estradiol
Dermal patch for a
period of 7 days
Only slight changes in serum-level over the
time of application. Systemic drug
exposure was 0.048 µg h/mL/d or 500 µg/d
for Estradiol-
Final Report No. KIST10000001, Schering AG,
Concentration of Levonogestrel and Estradiol in
rat serum following application of
estradiol/Levonogestrel transdermal
combination patches over a period of 7 days,
dated 09 Sept. 1999.
 
 
 
Circulating estradiol is bound to
sex hormone-binding globulin
(SHBG) and, to a lesser extent,
serum albumin. Only 1-2% of
circulating estradiol is unbound;
40% is bound to SHBG and the
remainder to albumin.
Carr, 1998. In: Wilson et al., eds,
Williams Textbook of Endocrinology,
9th Ed.,, W.B. Saunders
Co., pp. 751-817 as cited by
Toxicological Evaluation of certain
Veterinary Drug Residues in Food.
WHO Food Additives Series: 43,
prepared by the Fifty-second meeting
of the Joint FAO/WHO Expert
Committee on Food Additives
(JECFA), 2000
 
 
 

Estrogens are eliminated in faeces

and urine. The principal metabolites

found in urine are polyhydroxylated

forms conjugated at C3 to glucuronic

acid or sulfate. Elimination in bile is

subject to enterohepatic circulation,

and 20% of estrogens may be lost

through faecal elimination.

Lewis et al., 1998 Eur. J. Gastroenterol.

Hepatol., 10, 33-39 as cited by

Toxicological Evaluation of certain

Veterinary Drug Residues in Food.

WHO Food Additives Series: 43,

prepared by the Fifty-second meeting

of the Joint FAO/WHO Expert

Committee on Food Additives

(JECFA), 2000

 
 

 

Two main competing, irreversible

pathways for estradiol hydroxylation

are 2-or 4-hydroxylation and 16 alpha-

hydroxylation.

Michnovicz et al., 1989. Metabolism,

38, 537-541. 817 as cited by

Toxicological Evaluation of certain

Veterinary Drug Residues in Food.

WHO Food Additives Series: 43,

prepared by the Fifty-second meeting

of the Joint FAO/WHO Expert

Committee on Food Additives

(JECFA), 2000

Hamster,

in vitro,

liver

microsomes

 
 

Does dependency of metabolism.

16alpha-hydroxylation predominates

at low (< 25 µmol/L) concentrations,

whereas 16 alpha-and C2-hydroxylation

contributed equally to estradiol

metabolism at higher concentrations.

Butterworth et al., 1996Drug. Metab.

Disposition, 24, 588-594 as cited by

Toxicological Evaluation of certain

Veterinary Drug Residues in Food.

WHO Food Additives Series: 43,

prepared by the Fifty-second meeting

of the Joint FAO/WHO Expert

Committee on Food Additives

(JECFA), 2000.

Syrian

hamster

 

 

Metabolism in Kidney: 2-hydroxy

formation after catalysis by CYP1A1/2

and CYP3A

Hammond et al., 1997.Toxicol.

Appl. Pharmacol., 145, 54-60 as

cited by Toxicological Evaluation

of certain Veterinary Drug Residues

in Food. WHO Food Additives Series:

43, prepared by the Fifty-second

meeting of the Joint FAO/WHO

Expert Committee on Food Additives

(JECFA), 2000.

Mouse

CYP1B1

expressed in

E. coli

 

 

Significant differences in steroid

metabolism are seen between

rodents and humans.

Human but not mouse CYP1B1,

was identified as an estrogen 4-

hydroxylase,.

Savas et al., 1997. Arch. Biochem.

Biophys., 347, 181-192 as cited by

Toxicological Evaluation of certain

Veterinary Drug Residues in Food.

WHO Food Additives Series: 43,

prepared by the Fifty-second meeting

of the Joint FAO/WHO Expert

Committee on Food Additives

(JECFA), 2000.

Syrian

hamster,

in vitro,

liver and

kidneys

lysosomes,

male

 

 

Deconjugation of estradiol and

estrone glucuronides with rates

of 56% and 34%, respectively.

 

Demethylation of catechol estrogens

with fivefold higher rates in liver

than in kidney.

Zhu et al., 1996. Toxicol. Appl.

Pharmacol., 136, 186-193as cited

by Toxicological Evaluation of

certain Veterinary Drug Residues

in Food. WHO Food Additives

Series: 43, prepared by the Fifty-

second meeting of the Joint

FAO/WHO Expert Committee on

Food Additives (JECFA), 2000.

 
 
 
Redox cycling of catechol
(hydroxyquinone) to quinone
through semiquinone intermediates
is catalysed by oxidation of catechol
estrogens by peroxidases or CYP1A1
lipid hydroperoxide cofactors. Oxygen
radicals formed in this redox process
may increase the carbonyl content of
proteins, formation of DNA adducts,
and lipid peroxidation. It was concluded
that redox cycling is a critical step in
estrogen-mediated carcinogenesis.
Yager & Liehr, 1996. Annu. Rev.
Pharmacol. Toxicol., 36, 203-232
as cited by Toxicological Evaluation
of certain Veterinary Drug Residues
in Food. WHO Food Additives Series:
43, prepared by the Fifty-second
meeting of the Joint FAO/WHO
Expert Committee on Food
Additives (JECFA), 2000.
 
 
 
In general, estradiol is inactive when
given orally because it is inactivated
in the gastrointestinal tract and liver,
although fine-particle formulations of
estradiol are effective when given orally
and are used therapeutically. The
bioavailability of a single 4-mg dose
of fine-particle estradiol administered
orally to 14 young women was 5% of
that of a dose administered intravenously.
At least 60% of the absorbed dose
appeared in the serum as estrone and
estrone sulfate and was available as
part of the endogenous pool.
Estradiol shows little toxicity when
given as a single oral dose. Few
conventional short-and long-term studies
of the systemic toxicity of estradiol in
animals treated orally were available,
but there is sufficient information to
demonstrate that the reverse effects of
estradiol seen in animals are associated
with estrogenic activity. Because of the
specificity and affinity with which
estradiol binds to its receptors, the
hormonal effects occur at much lower
doses than other toxicological responses
and hence are the most appropriate for
use in evaluating the safety of the compound.
Toxicological Evaluation of certain
Veterinary Drug Residues in Food.
WHO Food Additives Series: 43,
prepared by the Fifty-second meeting
of the Joint FAO/WHO Expert
Committee on Food Additives
(JECFA), 2000.