Page 60 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Concepts in Veterinary Toxicology Chapter | 1 27

VetBooks.ir than use a traditional approach to attempt to precisely Veterinary Pathology (ACVP), to evaluate histological
specimens from representative cases and the diagnoses of
define a lethal dose 50% (LD 50 ), it has become customary
the original pathologist to verify that the diagnoses are
to use approaches with many fewer animals to define an
approximate LD 50 . In some cases, it may be desirable to appropriate and consistent with the scientific norm. As
determine the concentration of a test agent in water or air an aside, I encourage veterinary toxicologists to person-
that produces 50% lethality over a defined period of time, ally review the pathology findings in studies with the
a lethal concentration, LC 50 . This approach remains study pathologist so as to be familiar with the nature of
in common use when studying aquatic organisms. the pathology findings. However, I discourage veterinary
In modern toxicology, increasing attention is given to toxicologists from taking on a dual role of toxicologist
conducting studies with exposures that are defined by the and pathologist for a study. Indeed, this approach would
anticipated conditions of use of the test material. This be unacceptable for a study to be submitted for regulatory
may involve initially conducting a study of 2 weeks dura- purposes unless the toxicologist was also an ACVP
tion, perhaps with up to five exposure levels anchored by Diplomate.
a level related to anticipated use. The results of this study
are then used to select exposure levels, perhaps three or Describing Exposure Response
four, and to sharpen the focus of a 90-day study. The Relationships for Noncancer Endpoints
results of the 90-day study, in turn, are used to select the
exposure levels and sharpen the focus of a study of It is now appropriate to consider how the data generated
2-years duration. Although it has become customary to from toxicological investigations can be used. Let us first
conduct chronic exposure or 2-year studies with three examine a threshold exposure response relationship as
exposure levels, it should be recognized that use of a con- shown in Fig. 1.3 and shown now in an expanded form in
trol group and three exposure levels spanning a range of Fig. 1.10. The first step is to examine the data set from
concentrations differing by a factor of 2, i.e., 1, 1/2 and 1/4 critical exposure response studies to identify key para-
or a factor of 3, i.e., 1, 1/3rd, and 1/9th, does not provide a meters to be used to describe the results. Key determina-
robust data set for characterizing the shape of the exposure tions are the No Observed Effect Level, the highest
(dose)-response relationship. On the other hand, the use of exposure level for which no effects are observed and the
exposure levels differing by a factor of 10, i.e., 1, 1/10th, NOAEL, the highest exposure level that produces no
and 1/100th may provide an excessively broad range of adverse effects. Obviously, characterization of an effect
exposure levels for identifying a lowest observed adverse as adverse or not adverse is a matter of professional judg-
effect level (LOAEL) or no observed adverse effect level ment. For example, in a cholinesterase inhibitor study, is
(NOAEL) as will be discussed later. a reduction in blood cholinesterase in the absence of sali-
In chronic studies with rodent species, major attention vation or other clinical signs an adverse effect or merely
is directed to evaluating any toxicant-induced changes in an effect?
animals at the several exposure levels compared to con- In the absence of the identification of a NOAEL, there
trols over a 2-year period or until a defined mortality level is a need to identify the LOAEL, the highest exposure
is reached, such as 20% surviving. Any changes in vari- level at which an adverse effect is observed. The specific
ous indices of morbidity or pathological alterations will NOAEL and LOAEL that can be identified are a function
be evaluated compared to controls as well as tested for
trends across the exposure levels. In many cases, the pri- NOAEL (LOAEL)
RfD =
mary endpoint of concern will be cancer, which should UF × MF
include evaluation of all stages of tumor development up
to sarcomas and carcinomas. It has become customary to Response
use life table statistical methods such as that of Kaplan RfD LOAEL
and Meier (1958) to evaluate the incidence of key
changes. This approach allows for the use of data not
NOAEL
only from the survivors at the end of the study, but also
animals that have died or been euthanized at interim
Dose
times. This situation is analogous to that encountered in
human epidemiological studies when subjects may be lost UF = UF · UF · UF · UF L UF = LOAEL to NOAEL (10×)
H
A
L
S
to follow-up. UF H = Human variability (10×) MF = Modifying factor for
= Animal to human (10×) completeness of data (1–10×)
UF A
It has become customary when the results of chronic
UF S = Subchronic to chronic (10×) RfD = Reference dose
studies will be used for regulatory purposes to convene a
pathology peer review panel of expert veterinary patholo- FIGURE 1.10 Schematic rendering of a threshold exposure response
gists, typically Diplomates of the American College of relationship.