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PAG symposium on single-cell protein products for animal and human feeding

The Protein-Calorie Advisory Group of the United Nations system held an international symposium on the above subject on 31 March and 1 April 1977. The meeting was held at the Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy.

At the symposium, three issues were singled out for special review. They were:

(a) the utilization and safety of fatty acids with uneven numbers of carbon atoms in some hydrocarbon-grown yeasts;
(b) the significance and fate of residual paraffins found in some yeast;
(c) the strength of the evidence for lack of toxicity or carcinogenicity of the single-cell products currently proposed for animal feeding.

On each of these points the PAG Working Group on SCP, at its sixth meeting held in 1976, concluded that the data demonstrated convincingly the safety of the specific products reviewed at that time: Toprina, Liquipron, and Pruteen. At the present symposium, much additional evidence was presented which reinforced this conclusion.

Uneven carbon-chain fatty acids were shown to be utilized through normal metabolic pathways and to be mobilized in the same way as even carbon-chain fatty acids, both under normal conditions and during fasting or stress. Data were presented to confirm that rat-liver mitochondria utilized even and uneven carbon-chain fatty acids at about the same rate Moreover, liver and heart mitochondria of animals fed Liquipron-containing uneven carbon-chain fatty acids-respond to a number of chemicals which affect their metabolism in the same manner as those of control animals.

Previous data had established that the level and nature of residual paraffins of a chain length C14-C18 found in some hydrocarbon-grown SCPs have no effect on the viability or the respiratory function of cells, and disappear from tissues in a normal manner when they are no longer in the diet. At this symposium, data from additional studies, especially from Japan, were presented, which reinforced this conclusion.

A survey of the presence of normal paraffins in feedstocks and commercially available foods in Italy showed that a large variety of feedstocks, including fermented milk, fishmeal, hay, lucerne hay, tomato peels and others, contained qualitatively the same e-paraffins (C14-C18) as SCP and, in addition, a large range of other e-paraffins including C20-C30. For example, "turkey feed" contained about 70 ppm of e-paraffins; some commercially available samples of lard contained a range of comparable e-paraffins between 2 and 20 ppm; and samples of bovine fat of grazing animals contained from 2 to 202 ppm. The fat of swine and bovines fed with normal alkane-grown SCP contained levels of e-paraffins at concentrations of the order present in SCP and resulted very rapidly in a steady-state level which did not change over long periods of feeding.

The studies also revealed marked species differences in the rate of body use of e-paraffins. Rats metabolized e-paraffins slowly and therefore the accumulation of this material in the adipose tissue was greater than for farm species such as poultry and pigs, which were more effective in metabolizing e-paraffins, resulting in less accumulation in their fat Feeding hens with SCP results in e-paraffin concentrations in adipose tissue comparable to those found in animals fed controlled diets Similarly, the e-paraffin of fat of pigs fed SCP is equal to, or slightly higher than, the fat of pigs fed stock-diets And preliminary studies with the non-human primate Maccacus mulata also show lower levels than that observed in the rat That these e-paraffins are used as energy sources in these species is indicated by recoveries of up to 65 per cent for their carbon in respiratory CO2.

As is true for dietary fat in general, the accumulation in the adipose tissue represents only a very small fraction of the absorbed amount of e-paraffins (from 0.0015 to 3.0 per cent depending on the dose and species). It is also clearly established that e-paraffins present in SCP after omega oxidation are transformed into the corresponding fatty acids. These fatty acids follow normal metabolic pathways (oxidation and incorporation into triglycerides, phospholipids and cholesterol esters).

Since the normal alkanes, ethanol and methanol, proposed as feedstocks for the growth of single-cell proteins, are derived originally from petroleum, it is, of course, essential to be sure that even though highly purified they are free of any compound which might be carcinogenic. Even undetectable amounts (less than 1 part in 1,000,000,000) that might somehow be concentrated by the cells and have some biological activity have been sought by feeding studies of many thousands of mice, rats, quails, dogs, pigs, chickens, swine, calves, and even monkeys, in many different laboratories in Europe, Japan, and the USA, with no indication of carcinogenicity or toxicity associated with them. Multi-generation studies of rats have now reached 20 generations, and in quail, 30 generations, with no indication of an increase in tumours, change in reproductive capacity, or any other evidence of abnormality.

The present meeting reviewed additional studies from the Istituto "Mario Negri" in Milan, designed to test the potential carcinogenicity of Liquipron. Several animal species were employed and, in addition, in order to account for potential differences in response, both inbred and out-bred strains of mice were employed. Over 3,000 animals were used. Studies were carried out for the practical lifetime of the test animal to ensure that a maximum stress was applied to the system, and to establish whether the product could act as a co-carcinogen by potentiating the effect of known carcinogens. No protein source for animal feeding or human consumption has ever been subjected to such thorough testing. In no case did these products induce a carcinogenic or toxic response.

Existing methods of classification of yeast species, based on morphology and biochemical characteristics, were clearly inadequate to define homogeneous species. As a result, yeasts of quite different genetic composition were being assigned erroneously to the same species. Outstanding work presented at this symposium by workers from the United States and Japan indicated that by the capacity of single-strand DNA molecules from two different strains to re-associate, yeast species could be differentiated. These studies showed, for example, that the various strains reported to be Candida tropicalis in fact represented a number of different species. The organism used for Liquipron, originally identified as Candida novellus, has now been definitely confirmed as Candida maltosa It is unrelated to Candida tropicalis, whose complex of species has now been largely identified. Candida utilis, Candida maltose, and Candida lipolytica, the organism of Toprina, are all yeast species with no known toxigenic strains and can be clearly differentiated from all others by the new DNA recombination technique. They appear to be exceedingly safe organisms.

Persons with poorly controlled diabetes, undergoing immuno-suppressive treatment following organ transplants, undergoing corticosteriod therapy, or with other severely debilitating conditions, are at increased risk of acquiring fungal infections. Potentially pathogenic species such as Candida albicans, are ubiquitous in the environment, and pathogenic strains are associated with bird droppings, particularly those of pigeons, in an urban environment. Workers in SCP plants would appear, therefore, to be at far less risk from the benign species employed in production than from the potentially pathogenic species in the normal environment.

Although the end product of SCP plants for animal feeding will be killed organisms, it was reported at the symposium that large numbers of live cells of some of the same species can be injected directly into the bloodstream of rats at one time, or on repeated occasions, without producing an infection or permanent tissue damage. More significantly, there is no record of hazard to the health of workers in the brewing, wine-making, and cheese-making industries which have dealt with live yeasts of non-pathogenic species for centuries, and often on a very large scale in the twentieth century. Any other new organisms proposed for SCP production m the future will, of course, need to be subjected to the same stringent tests for infectivity and pathogenicity before acceptance, as has already been done with those presently proposed for animal feeding.

The symposium noted that in manufacturing operations involving any kinds of dust, including those associated with the production of cereal flours, oilseed meals, brewers' and bakers' yeasts and the like, good industrial hygiene practices call for minimizing the exposure of employees and monitoring both the health and the working environment. Since production of SCP requires establishment of large-scale manufacturing plants, it is important for these to conform to good operating practices. It is not that any special hazard to employees is envisaged in these plants, but only that a new industry cannot afford the consequence of any failure to establish and maintain appropriate environmental safeguards for its employees.

While SCP plants present no special problems caused by discharge of waste, their large scale requires careful attention to environmental considerations. Food-manufacturing practices and protection of the environment of industrial plants include a periodic sampling of effluents and surrounding air. For SCP plants, this will include periodic determination of the number of viable organisms in air and water, and their classification to ensure that the plant itself is not contributing significantly. With good manufacturing practice, there is no reason why SCP plants should constitute any threat to the environment in this regard.

The symposium reviewed, as objectively as possible, every kind of question or doubt which has been raised about the safety for humans and their environment of producing the single-cell proteins currently proposed for animal feeding, and the use of animal products derived from them. It concluded that all had been satisfactorily answered, and that for the specific products considered, further studies before authorization would not provide significant additional assurance of safety. The import of the seminar, and the specific conclusion of the PAG meeting that followed, was that there was no known scientific or nutrition reason not to proceed immediately with the production and sale of such thoroughly tested SCP products as Toprina, Liquipron, and Pruteen for animal feeding.

Single-Cell Protein for Human Feeding

The symposium devoted part of one session to considering clinical trials of new sources of protein for direct human use, focusing especially on the frequency of allergic responses to foods.

Candida utilis, known as a food yeast and produced in cane or beet molasses, or sulphite liquor, has been consumed by man for nearly a hundred years. It is a common component of processed foods in both Europe and America, and became a quantitatively significant food item in some European countries during World Wars I and II. It has never been associated with carcinogenicity or toxicity. This is also true of bakers' yeast and brewers" yeast and the many organisms, mainly yeast, consumed in wine and cheese. However, yeast, like any rapidly growing cell, has a relatively higher concentration than most foods of RNA (nucleic acid) which in man is excreted as uric acid; and while nucleic acids are essential components of all cells, and uric acid is a normal metabolite, excessive levels of the latter in blood and urine increase the risk of gout and kidney stones. The nucleic acid of food yeast and other SCP for direct human consumption can be reduced to that of many conventional foods by simple processing procedures.

Compared to most protein-containing foods, including milk, meat, eggs, legumes, and cereals, untreated yeast is remarkably low in properties allergenic for man. Work presented at the symposium showed that RNA reduction needs to be carried out in such a way as to ensure that this freedom from allergenicity is maintained. Alkaline hydrolysis at moderate temperature will apparently release protein fractions which cause gastrointestinal or cutaneous allergic response in some individuals. This can be prevented by carrying out the RNA reduction at higher temperatures, by acid-washing the material afterwards, or by subjecting it to the heat of extrusion under pressure. However, the evidence indicated that Candida utilis grown on molasses and subjected to RNA reduction at a temperature of 130 C was acceptable for food use as a protein source. In vitro procedures were described for monitoring the freedom of the processed material from allergenic tendencies. Such allergenic properties have nothing to do with toxicity, as has been demonstrated repeatedly by extensive feeding trials in several species of experimental animals. The latter, together with the clinical trials considered, provided evidence that properly selected, produced, and processed SCP can be safely fed directly to humans as a protein source with good nutritional results. The meeting emphasized, however, the importance of adequate pre-clinical studies in multiple species of experimental animals as proposed in PAG Guideline No. 6 (Preclinical testing of novel sources of protein!, followed by properly conducted clinical trials of acceptability and tolerance as indicated in PAG Guide line No. 7 (Human testing of supplementary food mixtures}. Only after these extensive tests have been satisfactorily completed can SCP be approved for direct human consumption if the SCP represents a new species, a new substrate, or merely a new method of processing

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