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Regulatory Aspects for the Drugs and Chemicals Used in Food-Producing Animals Chapter | 7 109

VetBooks.ir Antimicrobial Effects fraction of the dose available for colonic microorgan-
isms can be calculated as 1 minus the fraction (of an
Antimicrobial drug residues in contaminated foodstuffs
oral dose) excreted in urine. Human data are encour-
can lead to direct toxic effects. The impact may range
from sensitizing reactions to drug-inducing organ damage, aged, but, in their absence, nonruminant animal data
or both. Moreover, many trace amounts of antimicrobial are recommended. In the absence of data to the con-
drugs may have the potential to perturb the human gut trary, it should be assumed that metabolites have anti-
flora or to disrupt the barrier effect that it exerts, thus per- microbial activity equal to that of the parent
mitting the ingress of potentially pathogenic bacteria into compound. The fraction may be lowered if the appli-
cant provides quantitative in vitro or in vivo data to
the gastrointestinal tract. Antimicrobial residues in food
show that the drug is inactivated during transit through
constitute a variety of health hazards to humans that
the intestine (FDA, 2013).
depend on the frequency and degree of exposure. The two
MIC calculation (MICcalc). Calculation of the esti-
main risks related to antimicrobials are hypersensitivity
mated NOAEC (MICcalc) for colonization barrier disrup-
reactions, which appear in allergic individuals, and the
tion uses MIC values from the lower 90% confidence
acquisition of resistance by pathogenic microorganisms to
limit of the mean MIC 50 for the most relevant and sensi-
certain antibiotics. These effects may be studied using a
tive human colonic bacterial genera. The strains needed
variety of experimental models, and they can be taken into
to determine the MICcalc were chosen according to these
account in the calculation of the ADI value. Derivation of
guidelines, which state that an intrinsically resistant bacte-
a microbiological ADI (mADI) is only recommended if
rial genus should not be included (FDA, 2013). MIC data,
antimicrobial drug residues reach the human colon due to
obtained by standard test methods, from the following rel-
incomplete absorption, enterohepatic circulation, or secre-
evant genera of intestinal bacteria (Escherichia coli,and
tion across the intestinal epithelial mucosa and remain
species of Bacteroides, Bifidobacterium, Clostridium,
microbiologically active. The following formula is used to
Enterococcus, Eubacterium (Collinsella), Fusobacterium,
derive a mADI based on MIC or other in vitro data gener-
Lactobacillus, Peptostreptococcus/Peptococcus).
ated for the antimicrobial drug (see Fig. 7.1).
NOAEC (No Observable Adverse Effects Concentration). The standard human food safety assessment for new ani-
It is recommended that the NOAEC derived from the mal drugs accurately determines the safe concentration for
lower 90% confidence limit for the mean NOAEC from traditional toxicological endpoints as mentioned above.
the in vitro systems be used to account for the variability However, the impact of low levels of antibiotics on the
of the data. In this formula uncertainty factors are not intestinal microflora is not directly examined in these toxi-
generally needed to determine the mADI. cological studies. The human gastrointestinal tract ecosys-
Mass of colon content. The 220 g value is based on tem consists of complex and diverse microbial communities
the colon content measured from accident victims that have now been collectively termed the intestinal micro-
(Cummings et al., 1990). This total colonic volume of biome (O’Hara and Shanahan, 2006). The intestinal micro-
220 g is used to calculate the mADI, being a conserva- biome is an extremely complex and dynamic ecosystem
tive value. with a large and diverse group of microorganisms that
Fraction of oral dose available to microorganism include bacteria, archaea, fungi, and viruses. The intestinal
(intestinal microbiota). The fraction of oral dose avail- microbiome contains in large part bacteria that belong to the
able to intestinal microflora using in vitro and/or five phyla of Firmicutes, Bacteroidetes, Actinobacteria,
in vivo data. In the absence of data, 100% of the oral Proteobacteria, and Verrucomicrobia. Firmicutes and
dose is assumed to reach the colon in active form. It is Bacteroidetes constitute approximately 90% of the total
recommended that the fraction of an oral dose avail- community (Lagier et al., 2012). Therapeutic doses of anti-
able for colonic microorganisms be based on in vivo biotics can cause adverse effects on the intestinal microfloral
measurements for the drug administered orally. ecology (i.e., disruption of the intestinal microflora, or
Alternatively, if sufficient data are available, the effects on the metabolic activity of intestinal microflora).

NOAEC x Mass of colon content (220 g/day)
mADI =
Fraction of oral dose available to microorganism x 60 kg person

FIGURE 7.1 Derivation of a microbiological ADI from in vitro data.