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Biomedical subjects

P Krogh

Publications and source records attributed to P Krogh.

At least 19 recordsLinked to original sources

Role of ochratoxin in disease causation.

Under experimental conditions renal damage has been induced by alimentary exposure to ochratoxin A in all single-stomach animals tested so far, including rodents, dogs, pigs and birds, and even in young ruminants still functioning as single-stomach animals. Most information on ochratoxin-induced nephropathy has been obtained in pigs during experimental studies comprising structural as well as functional changes. The renal damage is characterized morphologically by atrophy of the proximal tubules, interstitial cortical fibrosis and sclerotized glomeruli, and functionally by impairment of tubular function indicated by a decrease in TmPAH/Cin and reduced ability to produce concentrated urine. The renal effect has been observed using exposure levels of ochratoxin A in the range 200 to 4000 micrograms/kg feed. Field cases of ochratoxin-induced nephropathy in pigs have been encountered in many countries, and the disease mycotoxic porcine nephropathy (MPN) is recognized as an endemic disease entity in several northern and central European countries. Epidemics of MPN have been reported, closely related to excessive climatic conditions in periods preceding harvest. Ochratoxin A is a recognized renal carcinogen in the mouse. In female pigs exposed to alimentary ochratoxin A for 2 years, no renal cancer was observed. Ochratoxin A is metabolized and excreted relatively fast in animals, with an RL50 (residue elimination) in the pig of a few days for various tissues. Past exposure data is a requirement in retrospective epidemiological studies, but because of the short RL50 values tissue analysis for ochratoxin A is unlikely to provide that kind of data, in animals or in humans. In order to meet this demand a procedure has been developed, using renal biopsy material for activity analysis of two renal tubular enzymes, phosphoenolpyruvate carboxykinase and gamma-glutamyl transpeptidase. In pigs exposed to ochratoxin A for 1 week a 40% reduction of the enzyme activity was observed. The dose-related activity decrease of the two enzymes was accompanied by a dose-related aggravation of renal impairment, as measured by a reduction of TmPAH/Cin, suggesting that these enzymes are sensitive indicators of ochratoxin A-induced nephropathy.

Animals

The role of yeasts in oral cancer by means of endogenous nitrosation.

Oral leukoplakias, particularly non-homogeneous types, are often invaded by yeasts, with Candida albicans being the dominant species. The more advanced precancerous leukoplakia lesions yield more rarely occurring biotypes of C. albicans, suggesting a causal role for these biotypes in the malignant transformation. N-nitroso-benzylmethylamine (NBMA) is a compound able to induce carcinoma of the esophagus and the oral cavity in the rat. The catalytic potential of yeasts, isolated from leukoplakia lesions and from normal mucosa, to produce NBMA from the precursors N-benzyl-methylamine and nitrite was assessed at pH 6.8. The yeast strains differed in nitrosation potential, ranking from 0 to 1.2 micrograms NBMA/10(6) cells. C. albicans strains of the more rarely occurring biotypes showed the highest nitrosation potential, whereas C. tropicalis, C. parapsilosis, and Torulopsis glabrata were ranked lower. Strains with high nitrosation potential were generally isolated from lesions with more advanced precancerous changes. Thus, further evidence is provided supporting the hypothesis that yeasts play a causal role in oral cancer by means of endogenous nitrosamine production.

Candida albicans

Tissue distribution of radioactivity from ochratoxin A-14C in rats.

Examination of the distribution of radioactivity in rat tissues during the first 24 hr after administration of ochratoxin A-14C demonstrated maximum accumulation in stomach and kidney. The highest counts were observed in stomach, lung, kidney, thymus, spleen and heart during the first 6 hr after treatment, whereas the brain, liver muscle, duodenum, jejunum, ileum, and cecum exhibited the greatest counts at 18 hr after toxin exposure.

Animals

Ochratoxin A contamination of foodstuffs in an area with Balkan (endemic) nephropathy.

Ochratoxin A is a nephrotoxic fungal metabolite (mycotoxin) occurring in foodstuffs. The compound is causally associated with mycotoxic porcine nephropathy, a disease comparable with a human kidney disease, Balkan (endemic) nephropathy. A survey of 768 samples of foodstuffs (cereals and bread), locally produced in an area of Yugoslavia where Balkan (endemic) nephropathy is prevalent, has revealed that ochratoxin A is constantly present in parts of foodstuffs. The mean frequency of ochratoxin A contamination of cereals in the study period was 8.7 per cent, but a pronounced annual variation was encountered, with frequencies of contamination up to 43 per cent. These contamination frequencies are higher than those reported elsewhere for foodstuffs for human consumption. Thus further evidence is provided to support the hypothesis that ochratoxin A might by a disease determinant of Balkan (endemic) nephropathy.

Adult

Porcine nephropathy induced by long-term ingestion of ochratoxin A.

Nine pigs were fed crystalline ochratoxin A in their feed at a concentration of about 1 mg/kg. Three pigs and their controls were killed after 3 months and 6 pigs and controls were killed after 2 years. A decrease of the ratio TmPAH/CIn, increased urinary glucose excretion and decreased ability to concentrate urine, occurred within a few weeks and aggravated slightly during the 2-year period. Changes in renal structure, characterized by degeneration and atrophy of proximal tubules, interstitial fibrosis and hyalinization of glomeruli, were progressive during time of exposure, but terminal renal failure was not reached. The kidney, liver, muscular and adipose tissue contained 3 to 27 microgram ochratoxin A/kg after 3 months of exposure. No further accumulation of ochratoxin A residue was found after 2 years of exposure.

Animals

Mycotoxicoses of animals.

Mycotoxicoses are intoxications caused by ingestions of foodstuffs contaminated with mycotoxins, i.e. toxic secondary metabolites of microscopic filamentous fungi (moulds). By field observations and by experimental testing, toxins or toxic strains of more than 100 species of fungi have been encountered. However, causal associations have so far only been established for a small number of mycotoxicoses in farm animals, and the more important mycotoxicoses are aflatoxicosis, facial eczema, mycotoxic nephropathy, and estrogenic syndrome. A full assessment of the impact of mycotoxins on the health of farm animals can hardly be made at present, because the amount of surveillance data from mycotoxicoses is very limited, due mainly to inadequate diagnostic criteria. A new set of criteria for the diagnosis of mycotoxicosis is proposed, which has been successfully applied in the causative study of mycotoxic porcine nephropathy.

Animal Feed

Balkan (endemic) nephropathy and foodborn ochratoxin A: preliminary results of a survey of foodstuffs.

Ochratoxin A is a nephrotoxic fungal metabolite (mycotoxin) occurring in foodstuffs. The compound is causally associated with mycotoxic porcine nephropathy, a disease comparable with a human kidney disease, Balkan endemic nephropathy. A preliminary survey of home-produced foodstuffs in areas of Yugoslavia revealed that contamination with ochratoxin A is more frequent in an area where Balkan endemic nephropathy is prevalent (endemic area) than in area where this disease is absent. This indicates higher exposure to foodborn ochratoxin A in the endemic area. Thus further evidence is provided supporting the hypothesis that ochratoxin A is a disease determinant of Balkan endemic nephropathyk0

Food Analysis

Mycotoxin tolerances in foodstuffs.

In most countries general legislation on food (and feed) prohibits the sale of products containing poisonous or harmful substances, which would include relevant mycotoxins as well. So far only aflatoxin has been dealt with specifically in legislation. The aflatoxin control may include all foods (and feeds) but is limited in most countries to certain commodities likely to be heavily contaminated, viz. oilseeds and derived products. The aflatoxin tolerances established for foods vary from zero (level set by analytical method) through 30 ppb to 50 ppb. Tolerances for feeds are generally higher.

Aflatoxins

Ochratoxin A residues in tissues of slaughter pigs with nephropathy.

Kidneys showing nephropathy changes were collected from slaughtered pigs at seven slaughterhouses in various districts of Denmark. Levels of ochratoxin A residues greater than 2 microgram/kg were detected in 21 out of 60 kidneys (35%). Ochratoxin A residues in liver, muscular and adipose tissues were calculated on the basis of the kidney concentration. Although the 21 kidneys containing ochratoxin A were condemned, the carcasses passed the meat inspection. Routinely only a small fraction of pigs exhibits nephropathy changes at slaughter, but the results of this study provide indirect evidence for a limited occurrence of ochratoxin A residues in commercial meat.

Animals

Experimental avian nephropathy. Changes of renal function and structure induced by ochratoxin A-contaminated feed.

One-day-old chickens were fed ochratoxin A-contaminated diets at 2 levels: 0.3 and 1 mg ochratoxin A per kg feed, for 341 days. The only observable lesion to develop was a kidney damage comparable with the naturally occurring avian nephropathy. The changes in renal function were characterized by impairment of glomerular and tubular function, indicated by a decreased inulin clearance, TmPAH and decreased urine concentrating capacity. The changes of renal structure included degeneration of the tubular epithelium accompanied by regeneration. At slaughter, the kidneys, liver and muscular tissue of the birds contained residues of ochratoxin A (up to 50 mug per kg). As all the birds would have passed the meat inspection because no macroscopical lesions were present, this represents a possible health problem.

Animal Feed

Experimental porcine nephropathy: changes of renal function and structure perorally induced by crystalline ochratoxin A.

Nine pigs were fed crystalline ochratoxin A in amounts corresponding to a feed level of 1 mg per kg for 3 months. The only observable lesion developed was a kidney damage, identical to the naturally occurring porcine nephropathy. The changes of renal function was characterized by impairment of proximal tubular function, indicated by a decrease of the ratio TmPAH/CIn, of the ability to concentrate urine, and by an increased urinary excretion of glucose. The decrease of the ratio TmPAH/CIn is correlated with time of exposure to ochratoxin A. The changes of renal structure were characterized by degeneration of the proximal tubules, leading to tubular atrophy accompanied by interstitial fibrosis. At the end of the experiment the kidney, liver, adipose and muscular tissue of the slaughtered pigs contained sizable amounts of ochratoxin A residues. As the pigs would have passed the meat inspection this represents a possible health problem. The changes observed in this study are identical to those observed by feeding to pigs grains naturally contaminated with ochratoxin A.

Adipose Tissue

Epidemiology of mycotoxic porcine nephropathy.

Mycotoxic porcine nephropathy is a renal disorder caused by ingestion of feed-borne secondary fungal metabolites, possessing nephrotoxic properties. The disease is present endemically in all areas of Denmark, but unevenly distributed, with frequency varying from 0.6 to 65.9 cases per 10,000 pigs in 1971. Epidemics were encountered in 1963 and 1971, apparently associated with excessive climatic conditions. The highest frequency of the disease is found among pigs from the smaller farms. Ordinarily the same farm delivers cases during only one year. Female pigs contract the disease more frequently than male (castrated) pigs. The epidemiology of mycotoxic porcine nephropathy shows similarities with the epidemiology of endemic Balkan nephropathy.

Animals

Spontaneous toxic nephropathy in poultry associated with ochratoxin A.

At a poultry slaughterhouse 14 birds with macroscopic renal changes were collected, and the kidneys were examined histologically and the muscular tissue was analysed for ochratoxin A residues. Out of 14 birds 5 birds had ochratoxin A residues ranging from 4.3 to 29.2 mug/kg. In 4 of these birds a toxic nephropathy was found characterised by atrophy and degeneration of proximal and distal tubules and interstitial fibrosis. The possibility of birds with ochratoxin A residues being presented for human consumption is discussed.

Animals