Page 54 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Concepts in Veterinary Toxicology Chapter | 1 21

VetBooks.ir (GLPs) in the conduct of research intended to be used for and toxicodynamic modeling. However, toxicodynamic
modeling is still in its relative infancy.
regulatory decisions. Both the FDA (2001) and the EPA
It is important to recognize that even with today’s
(TSCA, 1985; FIFRA, 1991) have requirements for the
use of GLPs. The FDA GLP requirements do not extend level of knowledge of these extrapolation issues, it is not
to exploratory, mechanism of action or efficacy studies. possible to estimate, with absolute certainty, the precise
The basic elements of GLPs are (1) the appointment by numerical level of human exposure to a given agent that
the institution of a study director, (2) the use of an inde- may be without any risk of potential harm or the level
pendent quality assurance unit, (3) the use of documented and duration of exposure that is estimated to produce
standard operating procedures, (4) a written protocol for a specific level of harm. This is generally recognized in
each study, and (5) preparation of a final report contain- contemporary safety/risk evaluation methodology such
ing a GLP compliance statement for each study. The use that conservative approaches are used in estimating safe
of GLPs is not required by FDA for studies with domestic levels of human intake of chemicals. By taking a conser-
livestock. However, investigators conducting studies vative approach to setting standards or providing guidance
using domestic livestock would be well advised to attempt to limit exposures, there can be a high degree of confi-
to adhere to the basic principles that undergird GLPs to dence that an agent can be used safely if used as intended.
help ensure the quality and reproducibility of the data Ultimately, all processes that develop guidance or stan-
being generated. dards to limit exposures and thus, limit disease require
In my opinion, scientists conducting exploratory or judgments to be exercised. In short, scientific information
basic research studies would be well advised to use the can inform the standard or guidance development process;
basic concepts of GLPs in their research. I make this rec- however, it cannot prescribe or dictate specific standards.
ommendation noting that time spent, at the beginning of a The establishment of an adequate margin of safety or
new research study, developing and documenting a proto- an acceptable level of risk involves value judgments that
col may be a sound investment in that it will suggest go beyond the science.
ways to improve the protocol and make it more efficient
for addressing the hypothesis posed. Time invested in Schematic Experimental Designs
ensuring that the research process and records are well
documented may be crucial in providing documentation The experimental design for testing of any specific
for filing a patent application. hypothesis must be matched to the hypothesis, the desired
Another option for acquiring useful toxicity data statistical power, and the resources available. Inevitably,
beyond conducting epidemiological or whole animal decisions on an experimental design involve making
studies is to conduct investigations in in vitro using difficult choices among options because of resource
tissues or cells from mammalian species, both humans constraints. It is important to seek statistical advice during
and laboratory animals, and using bacteria and yeasts. the design of a study to ensure the statistical design
An additional option is to conduct structure-activity is matched to the hypothesis being tested. In this section,
analyses on the new agent using the large data bank of two schematic experimental designs will be discussed
structure-activity information already available on other to illustrate some of the key issues that must be addressed
related chemicals. in planning toxicological studies. The discussion in both
All of the options outlined, to some extent, create cases will assume that the species to be used in the study
extrapolation issues. Even if studies are conducted in the has already been selected.
species of interest, it is typically necessary to extrapolate
from the high levels of exposure or administered doses Acquiring Toxicokinetic Data
studied experimentally to lower exposures or doses antici-
pated to be representative of intended use. It may also be The first conceptual design, Fig. 1.7, illustrates an
necessary to extrapolate from a relatively short period of approach to acquiring data for understanding the link
study, say, days or a few weeks, to the intended period of between exposure and internal dose, the kind of data that
use, over months or years. If the studies are not conducted can be used for toxicokinetic modeling. Recall the toxico-
in the species of ultimate interest, there is need to extrap- kinetic linkage in Fig. 1.1. The design shown is based on
olate between species. It may also be necessary to extrap- a single brief intake of the test agent. However, the design
olate observations made in a population of healthy can be modified for studying chronic intake of an agent.
individuals to a population that includes individuals A critical decision is the choice of the route of administra-
with preexisting disease or altered susceptibility to devel- tion or intake of the test material. Obviously, such studies
opment of disease. Some aspects of the extrapolation are most readily carried out with parenteral administration
between species and across exposure/dose levels may of the agent. This may be the most appropriate route for
be facilitated by physiologically based toxicokinetic a pharmaceutical agent that is to be parentally administered.