Page 143 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

110 SECTION | I General

VetBooks.ir The adverse effects of antimicrobials are a concern because only allowed on veterinary prescription for direct applica-
tions or in medicated feed. These restrictions are deemed
of the important role that the intestinal microflora play in
necessary, as antimicrobials may lead to the selection of
maintaining and individual’s health. Also, perturbation of
the intestinal microflora may compromise the effectiveness resistant bacterial strains in animals that could be trans-
of other drug therapies and thereby adversely affect public ferred to humans, by direct contact or via foodstuffs, and
health. Most studies of antimicrobial drugs and their effects subsequently lead to an impairment of the efficacy of
on the human intestinal microflora were performed with antibiotics used in therapy of human infectious diseases.
therapeutic levels of antibiotics. In contrast to the well-
documented negative effects of therapeutic doses of antibio-
tics, the effect of low levels (i.e., ppb or ppm) of antibiotics Hormonal Effects
on perturbing the intestinal microflora is not well defined. Growth-promoting hormones, such as steroids and xeno-
It is possible that low doses of antimicrobial agents, biotics, have been used legally and illegally to increase
such as those found as residues in foods, could alter intes- live-weight gain and feed efficiency in various species,
tinal enzyme activity and have an effect on certain hor- more intensively in cattle and to lesser extent in ovine,
mones and drugs, since in most cases the lowest doses at swine, poultry, and fish. Promoting steroid hormones can
which the perturbations in the intestinal microflora occur be divided into four groups of molecules: (1) natural
have not been determined. In order to ensure human food steroids (oestradiol-17β, progesterone, testosterone);
safety the FDA’s CVM considered data gathered from a (2) xenobiotics (trenbolone acetate and zeranol); (3) syn-
large number of compounds and determined that the max- thetic steroids (ethinylestradiol, methyltestosterone, chlor-
imum safe concentration for antimicrobial products is madinone acetate, and others); and (4) diethylstilbestrol
1 ppm in a total diet of 1.5 kg. This equals a maximum (DES) and related substances (hexestrol, dienestrol).
antibiotic dose of 1.5 mg/day from consuming residues in The endogenous steroid hormones have a wide range
food. This level of an antimicrobial residue in food should of actions that affect almost all systems of the body.
produce no effects on the intestinal microflora (Paige These hormones act by binding with high affinity and
et al., 1997). high specificity to protein receptors, located in hormone-
All antimicrobial veterinary products are assessed for responsive tissues. The toxicity or adverse effects of the
toxicological and pharmacological hazards as appropriate steroid hormones in humans are apparent even at physio-
to the drug class and to the specific drug under consider- logical concentrations. A physiological level of testoster-
ation. Those animal drugs with microbiological activity one contributes to acne, baldness, prostatic disease and
are assessed for the potential hazard of ingested residues prostate cancer, cardiovascular disease, and peptic ulcers.
altering the intestinal microbiome and promoting emer- Physiological concentrations of estrogens, and to a lesser
gence and selection for resistant bacteria in the gastroin- extent progesterone, have been implicated in premenstrual
testinal tract of humans. The antimicrobial substances tension, dysmenorrhea, and some cancers of the reproduc-
may give rise to transfer of antimicrobial-resistant micro- tive system, including uterine and cervical, and breast
organisms or resistance determinant associated with (Taylor, 1983). The estrogen induction of DNA adduct
animal-derived foods to humans. An ADI for chronic formation has been described. The endogenous hormones
exposure of antimicrobial drug residues in the human diet are regulated as promoters rather than primary inducers of
is needed. Typically the ADI used to regulate the residues cancer in hormonally sensitive tissues.
of the drug in food reflect the lowest ADI that could be The natural sex steroid hormones estradiol, testoster-
established based on the endpoints evaluated. In some one, and progesterone may be in use illegally for growth
substances, the lowest ADI value is based on the mADI promotion.
assessment of changes in the human intestinal micro- DES is perhaps the most widely known estrogenic
biome (FDA, 2013). growth promoting agent. It is structurally different from
Antimicrobial feed additives have been used in animal the endogenous estrogens in that it does not possess the
production for many decades because of their favorable fused steroid ring structure but rather two phenolic
economic effects in livestock production. Added in low hydroxyl groups, which gives DES a special orientation
doses to the feed of farm animals, they improve growth similar to estradiol. The relative binding affinity of DES
and performance and hence are known as antimicrobial for the estrogen receptor is 141% (vs 100% for estradiol),
growth promoters. Due to the emergence of microbes but DES is 10 20 times more active than estradiol via
resistant to antibiotics that are used to treat human and the oral route. DES is also metabolized to radical or
animal infections, the European Commission (EC) quinone intermediates that react with cellular macromole-
decided to phase out, and ultimately ban as of January 1, cules, including DNA (Metzler, 1984). DES is carcino-
2006, the marketing and use of antibiotics as growth pro- genic in humans and in laboratory animals. DES was first
moters in animal feed. Since then, the use of antibiotics is used therapeutically in pregnant women in the United