Page 144 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Regulatory Aspects for the Drugs and Chemicals Used in Food-Producing Animals Chapter | 7 111

VetBooks.ir States to prevent threatened abortion, and in the early particularly at the implantation sites. Misplaced implants
and repeated implanting, which seem to occur frequently,
1970s a clear link was discovered between adenocarci-
represent a considerable risk that highly contaminated
noma in women and their exposure to DES in utero
(Herbst et al., 1971; Meyers, 1983). Furthermore, it has meat could enter the food chain (EC, 2002a).
been shown that DES had other effects on chicken treated Zeranol and trenbolone have been tested for their
with DES, the most common being vaginal adenosis and mutagenic and genotoxic potential in various systems
other gross abnormalities of the reproductive tract with different endpoints. Both compounds exhibited only
(Herbst, 1976). very weak effects (EC, 2002a).
According to the Directive 2008/97/EC the following The new high-tech product bovine somatotropin, used
substances are prohibited: thyrostatic substances; stil- for the enhancement of milk production in cattle, is also
benes, stilbene derivatives, their salts and esters; and not authorized in the EU.
estradiol 17β and its ester-like derivatives (see Table 7.3).
The Opinion of the Scientific Committee on Carryover of the Feed of Coccidiostats
Veterinary Measures relating to Public Health (SCVPH)
(EC, 2002a) concluded that there is a substantial body of and Other Medicated Feed
recent evidence suggesting that 17β-estradiol has to be The regulatory concept of “carryover” is used specifically
considered as a complete carcinogen, as it exerts both to designate the transfer of traces of a pharmacologically
tumor-initiating and tumor-promoting effects, and that the active substance contained in a medicated feed to a non-
data currently available do not make it possible to give a target feed, while the term “cross-contamination” is to be
quantitative estimate of the risk to human health. The considered as a contamination resulting from a carryover
mutagenic and genotoxic potential of 17β-estradiol is a or from the transfer in feed of any unintended substance.
consequence of metabolic activation to reactive quinones. The best way to assess the carryover from feed to food is
The report concludes that 17β-estradiol is not essential in to determine from animal experiments the so-called
the production of food-producing animals because the use “transfer factors” of chemicals from animal feed to ani-
of the available alternatives (especially prostaglandins) by mal products. The “transfer factor” is expressed as the
practicing veterinarians is already quite common in the concentration of the chemical in the animal food products
member states and that the complete prohibition of the
(mg/kg wet weight) divided by the concentration of the
use of 17β-estradiol for food-producing animals would
chemical in the animal feed (mg/kg dry weight) (Leeman
have no, or only a negligible, impact on farming and ani-
et al., 2007). Different studies have shown that an entire
mal welfare (EC, 2002a). Studies on the metabolism of
contamination-free production of premixes and compound
17β-estradiol in bovine species indicate the formation of
feeds in existing multiproduct plants is not possible in
lipoidal esters, disposed particularly in body fat. These
practice (Strauch, 2002, 2003). Practical experience indi-
lipoidal esters show a high oral bioavailability in rodent
cates that in feed mills, residual quantities of medicated
experiments; thus, the consequence of their consumption
feed stuffs may be retained at various points along the
needs to be considered in a risk assessment (RA). It is
production line and end up at the beginning of the produc-
known that experiments with heifers indicated a dose- tion of another feed product, contaminating subsequent
dependent increase in residue levels of all hormones batches of meal as they are processed. One possible
TABLE 7.3 Substances not Permitted in the European Union (EU)
1. Substances having a hormonal (stilbenes, stilbene derivatives, their salts and esters, estradiol 17β and its ester-like derivatives) or
thyrostatic action, and of β-agonists (with derogations) (Council Directive 96/22/EC) (Directive 2008/97/EC)
2. Pharmacologically active substances listed in Annex, Table 7.2 of Commission Regulation (EU) No. 37/2010 (Aristolochia spp. and
preparations thereof, chloramphenicol, chloroform, chlorpromazine, colchicine, dapsone, dimetridazole, metronidazole, nitrofurans
(including furazolidone), ronidazole)
3. Antibiotic growth promoters (avoparcin, ardacin, zinc bacitracin, virginiamycin, tylosin phosphate, spiramycin, monensin sodium,
salinomycin sodium, avilamycin and flavophospholipol added to animal feed due to the fact that the use of these substances could lead
to the selection of resistant strains in animal and that this form of antibiotic resistance can present problems for antibiotics used in human
therapy (Council Regulation (EC) No. 2821/98))
Growth factors (quinoxaline-N-dioxides such as carbadox and olaquindox) presented a risk to consumers (possess genoto ´xico and/or
carcinogenic properties) to operators or to the animal itself (impairment of adrenal cortex function in pigs) (Commission Regulation (EC)
No. 2788/98)
4. Pharmacologically active substances not listed in the Annex, Table 7.1 (allowed substances) of Commission Regulation (EU)
No. 37/2010 (i.e., MRLs do not cover species and uses that were considered minor by the sponsors of the data)