OCHRATOXIN A
First draft prepared by
Dr Preben Olsen
Institute of Toxicology
National Food Agency, Ministry of Health, Soborg, Denmark
Explanation
Biological data
Biochemical aspects
Absorption, distribution, and excretion
Effects on enzymes and other biochemical parameters
Toxicological studies
Short-term toxicity studies
Long-term toxicity/carcinogenicity studies
Special studies on the mate reproductive system
Special studies on embryotoxicity/teratogenicity
Special studies on genotoxicity
Special studies on immune response
Observations in humans
Comments
Evaluation
References
1. EXPLANATION
Ochratoxin A is a mycotoxin produced by a variety of species of
the genera Aspergillus and Penicillium. It is found mainly in
cereal and cereal products, some pulses, coffee, cocoa, figs, nuts and
coconut products, but can also occur in meat and dairy products
derived from animals exposed to ochratoxin A-contaminated feedstuffs.
Ochratoxin A was first evaluated at the thirty-seventh meeting of
the Committee (Annex 1, reference 94), when a provisional tolerable
weekly intake (PTWI) of 112 ng per kg of body weight was established.
The assessment was based on the deterioration of renal function in
pigs, for which the lowest-observed-effect level was 0.008 mg/kg/
bw/day (a no-effect level was not observed). A safety factor of 500
was used in deriving the tolerable intake of ochratoxin A. At that
time the Committee recommended that efforts should be made to
highlight the need tor ensuring proper storage conditions for grain
and grain products. Furthermore, appropriate ochratoxin A residues
should be monitored to obtain better estimates of dietary exposure and
to identify populations at greater risk with a view to implementing
preventive measures. The Committee also encouraged further studies
aimed at elucidating the role of ochratoxin A and other mycotoxins in
nephropathy in pigs and humans, the mechanism of induction of tumours,
and the role of phenylalanine in antagonizing the adverse effects of
ochratoxin A.
In view of the increasing number of reports on the occurrence of
ochratoxin A in food commodities in several countries, the Committee
was asked to re-evaluate this substance. Ochratoxin A has been
evaluated by the IPCS (1990) and IARC (1993).
Since the last review additional data have become available and
are summarized and discussed in the following monograph addendum.
2. BIOLOGICAL DATA
2.1 Biochemical aspects
2.1.1 Absorption, distribution, and excretion
Inhibition of the microorganisms in the lower GI tract by
neomycin caused reduced hydrolysis of ochratoxin A to the non-toxic
ochratoxin alpha, and increased blood levels of ochratoxin A of rats
(Madhystha et al., 1992).
Whole body autoradiography using intravenous injection of
14C-ochratoxin A to rats resulted in the following distribution
after 24 h (in decreasing order of concentration): lung, adrenal
medulla, skin, liver, myocardium, kidney, salivary gland, adrenal
cortex, muscle, gastric mucosa, and bone marrow (Breitholtz-
Emanuelsson et al., 1992).
In feeding studies in hens, ochratoxin A was not found in eggs
(Krogh et al., 1976). In another study, it was found in eggs when
hens were fed large amount of ochratoxin A (10 mg/kg bw) (Juszkiewicz
et al., 1982). A study on tissue distribution of 14C-ochratoxin A
in laying Japanese quail, demonstrated specific retention of
unidentified radioactivity as a ring-shaped deposition in eggs,
indicating that the toxin could be deposited over a short time period
(Fuchs et al., 1988).
Egg-laying Japanese quail were given single oral doses of 0, 1, 5
or 20 mg/kg bw ochratoxin A. Six hours following administration, the
concentrations of ochratoxin A were 13 and 34 µg/kg in abdominal yolks
of birds given 5 and 20 mg/kg bw ochratoxin A, respectively.
Ochratoxin A was still found in abdominal yolks on day 4 after
ochratoxin A administration, and the mean ochratoxin A concentration
in abdominal yolks was 10-fold higher than in whole eggs. No
ochratoxin A was found in eggs of birds given 1 mg/kg bw ochratoxin A
(Piskorska-Pliszczynska & Juszkiewicz, 1990).
Lactating rats, treated orally with single doses of up to
250 µg/kg bw ochratoxin A, excreted ochratoxin A in the milk. The
milk/blood concentration ratios of ochratoxin A at 24 h and 72 h were
0.4 and 0.7, respectively. A linear relationship was found between the
concentration of ochratoxin A in the dam's milk and that in the blood
and kidneys of the pups at 72 h. The pups blood/milk concentration
ratio of ochratoxin A was approximately 6. At 72 h, the sucklings had
higher levels of ochratoxin A than their dams in both blood and
kidneys (Breitholtz-Emanuelsson et al., 1993a).
2.1.2 Effects on enzymes and other biochemical parameters
When ochratoxin A was added to isolated rat renal proximal
tubules in suspension, mitochondrial dysfunction was seen as an early
event in the process of nephrotoxicity. Mitochondrial impairment
apparently occurred at sites I and II of the respiratory chain.
Although lipid oxidation occurred before cell death, it did not seem
to be responsible for the toxic effect (Also et al., 1991).
Calcium homeostasis was studied in rats treated intraperitoneally
with a single dose of 10 mg/kg bw ochratoxin A or multiple doses of
0.5 to 2 mg/kg bw ochratoxin A. An increase in renal endoplasmic
reticulum calcium pump activity was observed, suggesting an
association with ochratoxin A-induced renal cytotoxicity (Rahimtula &
Chong, 1991).
In vitro studies using pig renal cortical explants indicated
that ochratoxin A inhibition of macromolecule biosynthesis (protein,
RNA and DNA) possibly was not due to impairment of cellular
respiration (Braunberg et al., 1992).
The effect of ochratoxin A on phenylalanine metabolism was
studied in isolated hepatocytes and in liver homogenates from male
rats treated in vivo. Both the hydroxylation of phenylalanine to
tyrosine and the subsequent metabolism of tyrosine, as measured by
homogenate oxidation, were inhibited when ochratoxin A, at a
concentration of 0.12 to 1.4 mM, was incubated with isolated
hepatocytes (Creppy et al., 1990).
Ochratoxin A enhanced NADPH or ascorbate-dependent lipid
peroxidation in rat liver microsomes and NADPH-dependent lipid
peroxidation in kidney microsomes in vitro, as measured by
malondialdehyde formation or oxygen uptake. It was suggested that
ochratoxin A stimulates lipid peroxidation by complexing Fe3+ and
facilitating its reduction. Subsequent to oxygen binding, an
iron-oxygen complex initiates lipid peroxidation. Cytochrome P-450,
free active oxygen species and free hydroxy radicals do not appear to
be involved in Fe3+-ochratoxin A stimulated lipid peroxidation.
Peroral administration of 6 mg/kg bw ochratoxin A to rats appeared to
increase in vivo lipid peroxidation, causing a 7-fold increase in
ethane exhalation (Rahimtula et al., 1988, Omar et al., 1990).
In in vitro studies using pig renal cortical tissue, ochratoxin
A and citrinin added singly or in combination at concentrations of
10-6 or 10-3 M, did not elicit consistent or strong synergistic
effects as measured by transport of tetraethylammonium and
paraaminohippurate ions or protein synthesis using 3H-leucine
(Braunberg et al., 1994).
The effects of the enzymes superoxide dismutase and catalase on
ochratoxin A-induced nephrotoxicity were studied. Superoxide removes
oxygen by converting it to hydrogen peroxide; this enzyme works in
conjunction with catalase which removes hydrogen peroxide within
cells. Rats were given by subcutaneous injection 20 mg/kg bw of each
enzyme, every 48 h, 1 h before gavage with ochratoxin A (289 µg/kg bw
every 48 h), for 3 weeks. Superoxide dismutase and catalase prevented
most of the nephrotoxic effects induced by ochratoxin A, observed as
enzymuria, proteinuria, creatinemia and increased urinary excretion of
ochratoxin A. The results indicated that superoxide radicals and
hydrogen peroxide were likely to be involved in the nephrotoxic
effects of ochratoxin A in vivo. The authors suggested that use of
superoxide dismutase and catalase might be considered for prevention
of renal lesions in cases of ochratoxicosis (Baudrimont et al.,
1994).
Subchronic administration of ochratoxin A to rats indicated that
the renal proximal tubule was not the main target of ochratoxin A
nephrotoxicity, although decreased capacity to eliminate ochratoxin A
may possibly result in a self-enhancing effect (Gekle & Silbernagl,
1994). The main renal effect of ochratoxin A in rats was found in the
"postproximal" nephron as measured by reduced glomerular filtration
rate, increased fractional water, Na+, K+ and Cl- excretion and
an increased dependence of the osmol clearance on urine flow. In
addition, ochratoxin A was able to block membrane anion conductance in
canine kidney cells in vitro (Gekle et al., 1993).
2.2 Toxicological studies
2.2.1 Short-term toxicity studies
2.2.1.1 Chickens
Groups of 10 broiler chicken given ochratoxin A at a dietary
concentration of 4 mg/kg for 2 months resulted in a mortality
rate of 42.5%. When the feed was supplemented with 0.8 or 2.4%
L-phenylalanine, the mortality rate decreased to 12.5 and 15%,
respectively (Gibson, et al., 1990).
2.2.1.2 Pigs
A total of 533 blood samples from slaughter pigs, each
representing one herd, contained more than 2 µg/ml ochratoxin A (mean
9.4 ng/ml) in 35% of the samples analyzed. The pigs were raised on
barley from the unusually wet crop of 1987 in Sweden. The study did
not attempt to correlate the ochratoxin A content in feed and blood
(Holmberg et al., 1990).
Blood samples obtained from 279 herds of pigs slaughtered at 9
slaughterhouses in Sweden were analyzed for ochratoxin A. In total,
14% of the pigs had levels of ochratoxin A > 2 ng/ml blood. The
highest level found was 215 ng/ml blood (Hult et al., 1992).
2.2.2 Long-term toxicity/carcinogenicity studies
2.2.2.1 Rats
Groups of Fischer F344/N rats (80/sex/group) were administered
ochratoxin A by gavage in corn oil at 0, 21, 70 or 210 µg/kg bw/day, 5
days/week for 103 weeks. Renal carcinomas were found in 16/51 male
rats dosed with 70 µg/kg bw/day and in 30/50 dosed with 210 µg/kg
bw/day; no carcinomas were found in the lower dose groups. In female
rats, renal carcinomas were less common with 0/50, 1/50 and 3/50
animals showing carcinomas at low, mid and high dose. Renal adenomas
were found in all groups of male rats, increasing in frequency with
increasing doses. In the female rats, renal adenomas were only found
in the two highest dose groups. Fibroadenomas in the mammary gland
were found in 45-56% of treated female rats, a significantly higher
percentage than in the control group (NTP, 1989; Annex 1, reference
94).
2.2.3 Special studies on the male reproductive system
An in vitro study using isolated testis interstitial cells of
gerbils indicated that ochratoxin A inhibited testosterone secretion
(Fenske & Fink-Gremmels, 1990).
Male rats treated by gavage with 289 µg/kg bw ochratoxin A every
second day for up to 8 weeks, showed a two-fold increase in testicular
content of testosterone, and an accumulation of premeiotic germinal
cells as measured by increases in alpha-amylase, ALP and gamma-GT
enzyme activities in testis homogenate. All of these effects were
indicative of a disturbance of the spermiogenesis (Gharbi et al.,
1993).
2.2.4 Special studies on embryotoxicity/teratogenicity
Quantitative assessment of neurons and synapses was performed in
ochratoxin A-induced microcephalic mice at 6 weeks of age. The mice
were derived from pregnant females treated intraperitoneally with 3 mg
ochratoxin A/kg bw on day 10 of gestation. The somatosensory cortices
of treated mice had fewer synapses per neuron compared to controls
indicating reduced dendritic growth (Fukui et al., 1992).
Prechondrogenic mesenchymal cells from the limb buds of 4-day
chick embryos were cultured together with ochratoxin A for 6 days.
Ochratoxin A inhibited the accumulation of cartilage proteoglycans and
general protein synthesis in a dose-related manner (Wiger & Stormer,
1990).
Rat embryos explanted on day 10 of gestation were cultured in a
medium containing ochratoxin A at concentrations of up to 300 µg/ml.
Dose-dependent reductions in protein and DNA content of embryos were
seen.
Induced malformations included hypoplasia of telencephalon,
stunted limb bud development and decreased size of mandibular and
maxillary bones. Cellular necrosis of mesodermal and neuroectodermal
structures was observed (Mayura et al., 1989).
2.2.5 Special studies on genotoxicity
Treatment of mice with oral doses of 0.6, 1.2 or 2.5 mg/kg bw
ochratoxin A caused formation of DNA adducts in the kidney and to a
less extent in the liver and spleen. The adducts were measured after
24, 48, and 72 h by use of a modified 32P-postlabelling method
(Pfohl-Leszkowicz et al., 1991).
The frequency of SCE was increased in human peripheral
lymphocytes, and mutagenic effect was induced in Salmonella TA1535,
TA1537, TA1538, TA98, and TA100 that had been incubated in the
presence of conditioned medium derived from hepatocytes exposed to
ochratoxin A (Hennig et al., 1991).
Significantly increased number of chromosomal aberrations in
lymphocytes of patients with Balkan endemic nephropathy were found in
comparison to healthy human subjects. Similar numerical and structural
aberrations were seen in chromosomes of lymphocyte cultures from
healthy donors that had been incubated in vitro with ochratoxin A.
Aberrations of the X chromosome were significantly more frequently
involved than any single autosome in lymphocytes from patients with
Balkan endemic nephropathy and in lymphocytes treated in vitro with
ochratoxin A. The authors concluded that the observation of sex-linked
chromosome aberration of the X chromosome, and never the Y chromosome,
may be associated with the often observed prevalence of females among
Balkan endemic nephropathy patients in endemic regions (Manolov
et al., 1991).
Several DNA adducts with the same RF values as those obtained
from mouse kidney after treatment with ochratoxin A were detected in
tumorous tissue from three kidneys and five bladders of Bulgarian
patients. In comparison, no DNA adducts were detected in 3
non-malignant kidney collected from 3 French human subjects
(Pfohl-Leszkowicz et al., 1993).
The SOS-DNA repair-inducing activity of ochratoxin A and of
structurally related compounds in E. coli strains suggested an
ochratoxin A-derived free radical rather than reduced oxygen species
as the genotoxic intermediate(s) in bacteria (Malaveille et al.,
1991).
Ochratoxin A, administered orally to mice for 45 days at dietary
doses of 1 µg/kg bw/day, induced chromosome abnormalities and a
decrease in the number of spermatocytes. Dietary supplementation with
vitamin C at a concentration equivalent to the human therapeutic dose
(10 mg/kg bw/day), significantly minimized the adverse effects of
ochratoxin A (Bose & Sinha, 1994).
Similar adverse effects were observed when ochratoxin A was
administered to mice at an oral dose of 1 µg/kg bw/day for 14 days.
The genotoxic effects were substantially reduced by concurrent oral
administration of 132 IU vitamin A/kg bw/day (Kumari & Sinha, 1994).
Ochratoxin A, ochratoxin a and seven structurally related
substances were assayed for SOS-DNA repair inducing activity in
E. coli strain PQ37. The results indicated that the presence of
chlorine at C-5 appeared to be one determinant of genotoxicity.
Furthermore, the results again implicated an ochratoxin A-derived free
radical rather than reduced oxygen species as the genotoxic
intermediate(s) in bacteria (Malaveille et al., 1994).
2.2.6. Special studies on immune response
Immunosuppression was observed in chicken fed diets containing
0.5 or 2 mg ochratoxin A/kg of feed for 21 days. Compared to controls,
treated animals had reduced total serum protein, lymphocyte counts,
weights of thymus, bursa of Fabricius and spleen (Singh et al.,
1990).
2.3 Observations in humans
The clinical picture of Balkan endemic nephropathy was
characterized by progressive hypercreatininaemia, uraemia,
normochromic anaemia, hypertension and edema (Radovanovic, 1991;
Tanchev & Dorossiev, 1991). Pathologically, the disease was described
as a bilateral, non-inflammatory, chronic nephropathy, in which the
kidneys were much reduced in size and weight. Diffuse cortical
fibrosis extending into the corticomedullary junction, hyalinized
glomeruli and severely degenerated tubules were seen (Vukelic et al.,
1991).
Mycotoxic nephropathy in pigs (Krogh, 1978) was not apparent in
Balkan nephropathy endemic areas in Yugoslavia, raising questions
about the role of ochratoxin A in the etiology of Balkan nephropathy
(Mantle et al., 1991).
An unidentified nephrotoxin produced by Penicillium
aurantiogriseum, which causes persistent renal histopathological
changes in rats, has been suspected of playing an important role in
Balkan endemic nephropathy (Mantle et al., 1991).
Serum samples collected in Yugoslavia during 1979 from
inhabitants of villages affected by Balkan endemic nephropathy more
frequently contained ochratoxin A (1-100 ng/ml, one sample with
1800 ng/ml) than those from control villages (1-5 ng/ml). Of the 1553
samples of foodstuffs locally produced in the endemic area during
1972-1978, 10.3% contained ochratoxin A at levels of 2-140 µg/kg.
(Plestina et al., 1990).
Thirty-eight out of 297 human subjects from three districts in
Sweden showed content of ochratoxin A in plasma varying from 0.3 ng/ml
to 6.7 ng/ml, the highest level being observed in one district. Based
on data on the average concentrations of ochratoxin A in human plasma
combined with data on the plasma clearance for ochratoxin A in
different animal species, a calculated daily intake of ochratoxin A in
the range of 0.03 to 0.35 ng/kg bw in humans was suggested.
(Breitholtz et al., 1991).
A survey in Sweden showed that 23/40 human milk samples contained
ochratoxin A at concentrations of 10-40 ng/litre. Thirty-nine blood
samples from identical milk donors were all positive for ochratoxin A
at levels of 90-940 ng/litre. The study did not include a correlation
between levels of ochratoxin A in milk and diet (Breitholtz-Emanuelsson
et al., 1993b).
Nine out of 50 samples of human milk collected from different
areas in Italy during 1989-90 contained ochratoxin A at concentrations
of 1.7-6.6 ng/ml. The survey did not include estimates of ochratoxin A
in the diets (Micco et al., 1991).
A total of 152 urine samples collected from patients with Balkan
endemic nephropathy or urinary tract tumours and from control families
were analyzed. Ochratoxin A (5-604 ng/l) was detected in about 33% of
samples, more often in endemic villages than in non-endemic ones. The
highest levels were detected in patients with Balkan endemic
nephropathy or urinary tract tumours. 4-Hydroxyochratoxin A, a
regularly observed metabolite of ochratoxin A in rats, was not
detected (Castegnaro et al., 1991).
The mean concentration of ochratoxin in human serum samples from
65 healthy subjects in Italy was 0.5 ng/ml, in comparison to 1.4 ng/ml
in serum from 28 hospitalized patients treated by dialysis for
impaired kidney function. The difference was statistically significant
(Breitholtz-Emanuelsson et al., 1994).
Surveys conducted in 1986, 1989 and 1990 in Bulgaria showed
that ochratoxin A was found, more frequently and at higher levels,
in blood from patients with urinary tract tumours and/or Balkan
endemic nephropathy than in blood samples from unaffected subjects
(Petkova-Bocharova & Castegnaro, 1991).
A survey in Yugoslavia during 1986-1990 showed that the frequency
of urinary tract tumours was higher among inhabitants of Balkan
nephropathy endemic areas (population, 10346) compared to non-endemic
areas (population, 98 713) (Ceovic et al., 1991).
Results from a case-control study in patients with Balkan endemic
nephropathy or urinary tract tumours and healthy human subjects from
endemic and non-endemic areas, indicated a genetic predisposition to
develop Balkan endemic nephropathy, as the ability of patients to
metabolize ochratoxin A correlated to human phenotypes of debrisoquine
metabolism (Nikolov et al., 1991).
3. COMMENTS
Since the last review a number of toxicological studies have been
conducted on ochratoxin A, including investigations on epidemiology,
genotoxicity and nephrotoxicity. Although the results of these studies
are important for understanding the biological effects of ochratoxin
A, the Committee did not consider that they justified any change in
the basis on which the previous assessment of the tolerable intake of
ochratoxin A was made. In addition, the Committee confirmed that
nephrotoxicity was the most sensitive effect of ochratoxin A and that
the increased incidence of both benign and malignant tumours seen in
the rat occurred at higher doses.
4. EVALUATION
The Committee reconfirmed the PTWI established at the
thirty-seventh meeting, rounded it off to 0.1 µg/kg bw, and
reiterated its request for further studies on ochratoxin A.
Grain should be stored under suitable conditions to keep
levels of ochratoxin A to a minimum.
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See Also:
Toxicological Abbreviations