Page 57 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

24 SECTION | I General

VetBooks.ir approaches for evaluating toxicity induced in different interrelationships. With clinical case observations, the ini-
tial emphasis is on the clinical findings: what is the
organ systems. The various guidelines developed by the
response and the need, on the basis of a differential diag-
USEPA, FDA, and NTP are useful references for these
specialized approaches. For example, the EPA has pub- nosis, to establish that a toxicant is or is not involved.
lished guidelines for evaluating carcinogenicity (EPA, The evidence for a specific toxicant may be based ini-
1996a), gene mutation (EPA, 1996b), reproductive toxic- tially on clinical findings complemented by gross nec-
ity (EPA, 1996c), developmental toxicity (EPA, 1991) ropsy findings potentially buttressed by histopathological
and neurotoxicity (EPA, 1995). The EPA is continually findings. The differential diagnosis of a toxicosis may be
reviewing and updating its guidelines for toxicity testing. strengthened by evidence of a marker of dose, i.e., urine,
Forty-nine harmonized health effects test guidelines used blood, or tissue levels of suspected toxicant. The diagno-
in the testing of pesticides and toxic substances have sis may be further strengthened with evidence of expo-
been developed and can be found on the EPA Office sure, i.e., the presence of the toxicant in the feed or
of Prevention, Pesticides and Toxic Substances website identification of a poisonous plant or in the tissues of an
(EPA/OPPTS, 2006). exposed subject. At each step, the qualitative evidence of
The FDA has provided specific guidance for evaluat- a toxicosis and a specific toxicant is enhanced as qualita-
ing the safety of compounds used in food-producing ani- tive findings are supplemented by quantitative findings.
mals (FDA, 1994) and principles for evaluating the safety The analysis is not completed there, though. Other reason-
of food ingredients (FDA, 2011). The EPA has provided able differential causes of the same or similar clinical
guidelines for evaluating the safety of products intended signs must also be “ruled out” if the animals or humans
for use with cats and dogs (EPA, 1998) and domestic live- are in a real world or field setting.
stock (EPA, 1996d).
A special issue of concern with pharmaceutical pro- Quantifying Exposure
ducts is the presence of trace contaminants and whether
these trace contaminants should be tested individually. Quantitation is paramount in evaluating exposure. In the
One approach to addressing this issue is the use of a experimental setting, quantitation is considered beginning
“threshold of toxicological concern” concept championed with the design of the study and continued through all
by Kroes et al. (2005). Kroes, now deceased, was a Dutch aspects of the experimentation. To the extent feasible,
veterinarian who developed an excellent reputation in exposure to the toxicant should be rigorously character-
safety and risk assessment. The concept of “safety qualifi- ized. This starts with physical and chemical characteriza-
cation thresholds” (Ball et al., 2007, 2012) developed out tion of the test material, be it an alleged pure compound
of the “threshold of toxicological concern” concept. It is a or a mixture, including identification of any contaminants.
promising approach to minimizing the use of laboratory The exposure circumstances need to be rigorously
animals in exhaustive testing while still assuring the characterized. This, of course, is easiest to do when the
safety of pharmaceuticals. The European Medicines test material is administered by injection. Even with
Evaluation Agency (EMEA, 2004) has provided detailed injection, care must be taken to ascertain that the desired
guidelines for addressing genotoxic impurities. quantity of toxicant was actually injected. The quantity
The various guidelines are useful for planning safety administered is typically related to the body weight of the
evaluation studies. However, the guidelines should not be subjects.
used as a substitute for the use of professional judgment With administration by routes other than injection, the
in planning, conducting and interpreting toxicological situation becomes more complicated. This may involve
investigations. As noted earlier, toxicology is not a providing the experimental subjects’ feed to which the
“cookie cutter” or “check the box” science. toxicant has been added. If this approach is used, samples
of the contaminated feed should be collected periodically
for analysis of the test agent. In some cases, the concen-
TOXICOLOGIC DESCRIPTORS tration of the test agent in the feed will be used as a mea-
sure of the exposure. To accurately quantify exposure,
Toxicology Rooted in Observations
it will be necessary to know the concentration of the test
The results of toxicological investigations, either from agent in the feed and also determine the quantity of the
clinical case observations or planned experimentation, contaminated feed containing the test agent that has been
involve describing the exposure, the dose, the response, ingested. For dermal administration, it is necessary to
and interrelationships among these parameters. Exquisite know the concentration of the test agent in the liquid
knowledge of exposure or dose or response is not suffi- media applied to the skin and the quantity of the media
cient. Ultimately, it is necessary to understand their applied to the skin.