Environmental quality and safety. Supplement最新文献

It has long been known that certain estrogens and testosterone may increase, or sometime decrease, the incidence of neoplasmas in laboratory animals. They probably act by switching-on inappropriate genetic information or switching-off appropriate genetic information contained in nucleic acids. For instance, they may switch-on in adult animals information which is relevant only to a certain stage of embryogenesis or they may facilitate the expression of oncogenic viruses which would otherwise lay harmlessly dormant. The situation is rendered complex because an effect on one endocrine gland leads to effects on others so that factors which favour tumour development may result indirectly from administration of an anabolic or other hormonal agent. Two kinds of neoplasm are now known to be associated with human exposure to anabolic agents: vaginal adenocarcinoma and liver-cell tumours. Tumours of both kinds are among the spectrum of neoplasms that has been seen in laboratory animals exposed to agents of the same kind. In both animals and man there is evidence that tumours arising in response to anabolic agents are sometimes, initially at least, hormone-dependent. The evidence that 17beta-estradiol, diethylstilbestrol, chlormadinone, and testosterone are carcinogenic for laboratory animals is briefly reviewed and the reader's attention is directed towards the 1974 IARC Monograph on the evaluation of sex hormones for carcinogenic risk to man where the same evidence is reviewed more extensively. The significance for man of the results of studies on laboratory animals is discussed with special reference to the use of anabolic agents in meat production. Non-residue uses are to be preferred, as are naturally-occurring agents as opposed to compounds which do not occur in nature. More information is needed concerning the possible effects of prolonged exposure to very low doses of anabolic agents.

The various anabolic agents used in food-producing animals may differ in terms of toxicological considerations related to evaluating human safety. Aside from initial toxicological testing, after chemical characterization of the compound to be administered and its related metabolites expected to occur as residues in food, most synthetic anabolic agents are subjected to chronic/carcinogenicity testing because of usage pattern likely to lead to the occurrence of residues in derived edible products. Initial testing requirements include acute and subchronic studies in appropriate rodent species including a reproduction test with the first generation offspring tested for 90 days post-weaning. This subchronic study serves to indicate potential problems with reproductive performance, foetal toxicity, birth deformities, and other chronic or preneoplastic conditions. The Food and Drug Administration (FDA) may grant approval for certain usages of specific compounds using a 2.000-fold safety margin in relation to a "no deleterious effect" level from the subchronic studies, with upper residue limits of 0.1 ppm in tissue and 0.01 ppm in milk or eggs if there are no indications that further testing should be required. If higher residue limits are requested, the petitioner must perform lifetime testing in two rodent species including in utero exposure and a minimum of three dose levels. Other rodent offspring should be carried for a total of three generations. A six to twelve month study in a non-rodent population is required. Teratology studies might be rquired in at least two species. If no carcinogenic potential is observed, a 100-fold safety margin in relation to the no effect level is generally accepted as the safe exposure level for residues. Should a statistically significant increase in tumors be observed in the test animals as compared to controls, the compound will be classified as a carcinogen or a suspect carcinogen depending on histopathological observations...

In the U.S.S.R. the research activities on the use of anabolic agents have been carried out only on an experimental basis by agricultural and human medicine research centres. The evaluation of the animal products from the biological point of view consisted of: 1. evaluation of the biological effect on the laboratory animals; 2. assessment of the breakdown and role of the anabolic agents in muscle tissue and the estimation of the residue amounts of the anabolic agents in meat after slaughter; 3. evaluation of the biological quality of meat obtained from treated animals. Taking into account the above-mentioned directions of the research activities, the influence of diethylstilbestrol was taken into consideration. It has been concluded that the use of diethylstilbestrol leads to detrimental results from the medical authorities' point of view.

Pituitary growth hormone (GH) has considerable potential as an anabolic agent in animal production. For example, pigs treated with GH will grow faster (i.e. deposit protein), require less feed per unit of body weight gain, and will have less carcass fat than untreated animals. Lactating cows will produce more milk with less feed. It is likely, though not completely established, that young cattle will also respond to GH treatments. Most of the information on the mode of action of GH has been obtained with laboratory rather than farm animals. The hormone affects almost all aspects of metabolism although the specific mechanism for these effects is still not understood. Stimulation of protein accretion is reflected by increased nitrogen retention and incorporation of radioactive amino-acids into tissue proteins. An increased rate of protein synthesis is thought to be a result of enhanced ability of ribosomes to translate messenger RNA. GH increases polyamine synthesis by increased ornithine decarboxylase activity; RNA synthesis by increasing RNA polymerase and DNA synthesis by increased DNA polymerase. Cell division is stimulated in several tissues (e.g. muscle and lymphoid tissue). In vivo GH lowers the respiratory quotient indicating an increased oxidation of fatty acids. The numbers of fat cells do not change but the fat cells are reduced in size. The stimulating effects of GH on skeletal tissue, and perhaps other tissues as well, is mediated by the formation of at least three peptides called somatomedins. GH is a protein with a molecular weight of about 22,000 and contains 191 amino-acid residues. The amino-acid sequence varies with the species. GH isolated from one species is not always effective in a different species. Use of GH isolated from pituitaries does not appear to be economically feasible. A chemical synthesis for human GH has been accomplished. However, biological activity equivalent to the native hormone has not been unequivocally established. Synthesis of bovine or porcine GH is feasible but will be expensive. A partial sequence of GH with 39 amino-acid residues has some biological activity. Synthesis of this shorter peptide would be considerably less expensive. Since proteins generally are not active orally, an economic procedure for prolonged parenteral administration would have to be devised. Althernative approaches would be the stimulation of endogeneous production of GH with hypothalmic GH releasing factor. This factor has not been identified but is probably a small peptide. Agents such as arginine, DOPA, and prostaglandins, which are known to stimulate GH release under some conditions, could also be considered. Another approach would be the implantation of sparganum from the spirometra family (a flatworm). This treatment is known to mimic GH effects in the rat. Implantation of a GH producing tumour could also be considered. Clearly these latter suggestions are quite speculative and would present some obvious problems...<

When used in connection with animal production the term "anabolic agents" covers a wide range. Ther steroidal male and female sex hormones are included in this list, as are the nonsteroidal estrogens. For the clinician and for the endocrinologist, anabolics are only steroids chemically related to testosterone and 19-nortestosterone. Estrogens, though possessing anabolic properties, too, do not belong to this class. This paper will deal with anabolic agents in in the stricter sense of which mainly trenbolone acetate combined with hexestrol has been recommended for bull and heifer fattening. To consider possible consumer injury from ingestion of meat from anabolic agent treated animals, it is necessary to know the pharmacological properties of the agents, the doses producing certain effects or might produce, and the levels of residues in the meat. Trenbolone acetate will be compared with the following anabolic agents: methenolone acetate, methandrostenolone, nandrone, androstanazole, and 19-nortestosterone. The activity spectrum of trenbolone acetate is similar to that of 19-nortestosterone or those anabolics that are derived from 19-nortestosterone. The compound has about three times stronger androgenic effect than testosterone propionate. Its index of dissociation between anabolic/androgenic activity is 2--3. This index is 3--10 for the other anabolic agents. As regards the virilizing potency, trenbolone acetate is also on the top of the list. It seems that androgenicity and degree of virilization run paralle. The antigonadotropic activity (inhibition of ovulation and testicular growth) of trenbolone acetate exceeds that of testosterone propionate by the factor 3. The compound is not estrogenic and seemingly not or only weakly progestationally active. In principle, the androgenic activity (symptoms of virilization) as well as the antigonadotropic effect (disturbances of the menstrual cycle in women, inhibition of spermiogenesis in men) of trenbolone acetate might be noted. This risk, however, can be excluded by mere calculation. In rats, 0.1 mg/kg trenbolone acetate have an antigonadotropic effect. This corresponds to a daily dose of 5--7 mg in humans. By the same extrapolation, a daily human dose of 100 mg can be calculated for androgenic activity. Such factors of conversion are, of course, not precise because rats are much less sensitive to androgens and anabolics than humans. Thus, testosterone propionate is active only in daily doses of 10--20 mg. If in humans trenbolone acetate also has three times the activity of testosterone propionate, effects in man had to be counted with not less than a daily intake of 3--5 mg trenbolone acetate. The dose which is recommended for livestock fattening is 300 mg. IT can, therefore, be excluded almost with certainty that the meat would contain such large amounts of hormone residues.

In many countries anabolic agents are successfully used to increase the rate of growth of cattle. In the past widespread use was made of cheap synthetic estrogens such as diethylstilbestrol and hexestrol. However, new legislation in certain countries has restricted the use of synthetic estrogens. This has resulted in an intensive search by industry for alternative agents. On the one hand natural steroid hormones like estradiol, testosterone and progesterone were studied, while on the other hand products like an active compound of the resorcyclic acid lactones and the synthetic anabolic steroid trenbolone acetate were developed. Administration of anabolic agents to cattle is done in three ways. (1) The agent may be fed orally by incorporation into the concentrate feed or as a simple additive top dressing. If the agent is metabolised in the rumen, oral administration may still be possible by using coated materials which avoid rumen metabolism with subsequent absorption of the steroid from the small intestine. (2) The agent may be administered as a slow release implant, e.g. trenbolone acetate or various combined preparations of an androgen and estrogen. (3) Administration by repeated injection. This latter method is often impractical. Anabolic agents are normally administered to beef cattle or culled dairy cows during the last few months of the finishing period. Maximum weight gain performance in different types of cattle requires selection of the correct anabolic agent. Increased performance in female cattle is better when an androgenic steroid is administered. However, in intact males (bulls) best performance is only obtained when an estrogen, alone or in combination with an androgen, is administered. Castrate animals (steers) do best if a smaller amount of estrogen is combined with an androgen and administered, however there is evidence that androgen alone is as effective. In summary therefore, an additional response in growth of cattle may require the presence of an estrogen, as endogenous estrogen in the female and the exogenous form in the male. Only when this condition is met will administration of androgenic anabolic steroids result in maximum benefit, often improving the effect of estrogen given on its own. Anabolic agents have some beneficial effect on appetite. They may not affect the digestive processes of the alimentary system. They have a positive effect on nitrogen retention. The liver almost certainly has a central role in the regulation of nitrogen retention. Recent experiments suggest that urea entry rates in ruminants may be lowered, thus making available more nitrogen for protein synthesis. Muscle protein synthesis is altered with changes in carcass conformation. There are some changes in fat redistribution. How all these processes are integrated is not yet known. The possibility that anabolic agents establish a new hormonal status which is favourable to growth will be discussed...

In a series of experiments with a total of 1480 veal calves, different aspects of treating calves with anabolic steroids were examined. The anabolics used were 17beta-estradiol (E), trenbolone acetate (T), progesterone (P), testosterone (Te), C+T, E+P, E+Te and zeranole (Z). The N-retention was estimated by examining the urea: creatinine ratio in single urine specimens during the course of two feeding trials. Increased gain due to the treatment with E (20 mg implanted/calf) + P (200 mg) and Te (200 mg), respectively, E + T (140 mg) or Z (36 mg) was during the whole experimental period. The extra gain, due to anabolics seems to contain even more protein. This conclusion may be supported by the crude protein content of meat samples. The antibody production of a total of 311 male and female calves was investigated after the application of the following steroids: E (20 mg), T (200 mg), T (200 mg), E + T, P (200 mg), Te (200 mg), E + P, E + Te, and Z. Eleven days after the implantation of the steroids the animals were immunized with alumprecipitated human serumalbumin. Antibody-titres were determined by the Antigen-Binding-Capacity Test on day 14 following immunization. In nearly all groups the antibody-titres of female calves exceeded those of male calves on the average by 75%. The immune response of all experimental groups did not differ significantly from that of the corresponding control groups. However, the results indicate that both E + T and its single components E and T exert an immunodepressive effect in male calves. While the humoral antibody formation in the calf appears not to be influenced by anabolic steroids, it cannot be decided presently whether these substances effect cell-mediated immune reactions and/or unspecific mechanisms of resistance. When estradiol (20, 200, and 500 mg) and trenbolone acetate (140, 1400, 3500 mg) alone and in combination were implanted in female calves, blood glucose, GOT, GPT, alkaline phosphatase, LDH, cholesterine and bilirubine; Hb, PVC, quick value; urine density and pH were not affected by treatment. Some criteria of the mineral metabolism (Ca- and P-levels in serum and bone) was not altered by treatment. Trenbolone (1 400 and 3 500 mg), especially with estradiol, caused a decrease of the serum Mg-level and of the Mg-deposition in the bone. It is discussed that Trenbolone affects the dig-metabolism of calves. Some morphological findings are worth mentioning. The weight of uterus was not affected by the different doses of E or T, but a combination E + T led to a surprising weight increase. The proliferation of uterine glandular cells was responsible for the increased uterine size. The lumen of uterus was partially filled with a watery liquid. The reduction of the ovarian weight was accompanied by a diminution of follicular size for all treated calves, most evident for E (200, 500 mg) + T (1400, 3500 mg). A decrease in the number of follicles was also found for these two groups. T (3500 mg) caused a

Experiments were carried out to test the effect of implantation of Implix¿ (20 mg estradiol + 200 mg testosterone) or Revalor¿ (140 mg trienbolone acetate + 20 mg estradiol) on growth, feed conversion, slaughter quality, and residue levels in black Friesian bull calves at 4, 8, or 4 and 8 weeks before slaughtering. Weighings and calculations of feed conversion were carried out weekly. The control group of weight gain and feed conversion consisted of 22 calves; the chemical analyses of the control group was restricted to 8 animals. Implantation of the hormones at 4 or 8 weeks before slaughtering resulted in a significant beneficial effect on weight gain, feed conversion and carcass index over the control. This effect was improved (up to 15%) by implanting the hormones at 8 and 4 weeks before slaughter. The effects obtained with Revalor seemed to be superior to those obtained with Implix. In 75% of the treated animals, some remainder of implants was found. No effect was found on water binding capacity and colour of raw meat. Carcass quality was not significantly improved as judged from water, fat, ash, and protein content of the M. Longissimus Dorsi. The collagen content of the animals treated with Revalor was slightly, though not significantly, increased. There is a slight decrease in the relative bone content of the treated animals over the control resulting in higher meat percentages. Residues were determined in meat obtained from rib and neck by biological and chemical methods. Oestrogenic activity was found in only 7 samples from the neck; all samples from the rib were negative. Chemical examination indicates the presence of oestradiol in these samples. No residues of trienbolone could be detected in the meat samples. The Pars Dissiminata of the prostate was examined histologically on frozen and paraffin sections. Although the latter permitted a sharper interpretation, both methods indicated an increased activity of the prostates induced by hormone treatment. Compared to Implix, Revalor treatment provoked a more pronounced mucous activity. In recent years, the administration of estrogens in combination with testosterone or with trenbolone acetate (androst-4,9[10]-11-trien-3-one 17-acetate)2,3,4,17 has been shown to improve the growth rate and feed conversion5,14,17 in farm animals. However, there is a lack of information on carcass quality, which is of interest to the producer as well as to the consumer. Moreover, there are sample data14 about the residue levels remaining in the carcass following hormone implantation. These experiments were carried out to test the effect of the implantation of Implix¿ (20 mg estradiol + 200 mg testosterone) or Revalor¿ (140 mg trienbolone acetate + 20 mg estradiol) on growth, feed conversion, slaughter quality, and residue levels in black Friesian bull calves.