Page 50 - Veterinary Toxicology, Basic and Clinical Principles, 3rd Edition

Concepts in Veterinary Toxicology Chapter | 1 17

VetBooks.ir content are sufficient to provide input for estimating lim- toxicodynamic or pharmacodynamic models. It is obvious
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that multiple pathways and interactions may be involved
its of daily intake of I
in forage by the cows in order to
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content of milk to some prescribed limit
limit the I
in a toxicant producing disease and that knowledge of the
such as an Intervention Level as will be discussed later. individual steps and interactions will increase as knowl-
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Because the physical half-life of I is quite short, 8.06 edge of basic biological mechanisms increase. For exam-
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days, and the I is concentrated in the thyroid and milk ple, the explosion of knowledge of basic biology at the
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concern does not develop for the I content of the rest level of the genome (genomics), proteins (proteomics),
of the carcass. If the radionuclide or specific chemical and metabolism (metabolomics) has provided a basis for
were found in edible portions of the carcass, then infor- exploring the mechanistic basis of toxicant-induced dis-
mation on the radionuclide, chemical, or metabolite of the ease with a degree of refinement that could not even be
chemical in the edible tissues such as muscle would be of envisioned even a few years ago. In recent years, the
interest. For example, cesium behaves like potassium and, picture has become even more complicated, as it has
thus, concern exists for radiocesium concentrations in become apparent that mammalian organisms contain large
muscle as well as milk. Strontium behaves like calcium, and diverse populations of microbes that may influence
thus, concern exists for radiostrontium in milk and normal function and disease process; hence concern
in skeleton. for the “microbome.”
The characterization of the kinetics linking exposure Later chapters review the basic mechanisms of toxic-
with dose is referred to as toxicokinetics (for a toxic ity. In addition, many of the chapters on organ toxicity
agent) or pharmacokinetics (for a pharmaceutical). In and specific toxicants contain detailed information on
actual practice, the term pharmacokinetics is frequently mechanisms of toxicity. As the reader reviews this mate-
used when it would be more appropriate to use the term rial, and especially the detailed discussion of biochemical
toxicokinetics. Several chapters in the book deal specifi- mechanisms of action, it will be important to place those
cally with kinetics of toxicants and pharmaceuticals. in the context of processes at the cellular and tissue level:
Toxicokinetics (see Fig. 1.1) are used to describe the i.e., inflammation, cell death, cell proliferation, hypertro-
movement and disposition of the toxicant in the organism. phy, hyperplasia, metaplasia, and neoplasia. A strength of
This includes consideration of the route of entry: inges- the veterinary medical curriculum, as with the human
tion, inhalation, dermal, or purposeful administration by medical curriculum, is the emphasis given to understand-
injection. A complete description of the toxicokinetics of ing both normal body processes and disease processes
a toxicant will take into account (1) the intensity and extending from the molecular level to cells to tissues to
duration of the exposure; (2) the rate and amount of organs and, ultimately, to the integrated mammalian
absorption of the toxicant from the site of entry; (3) the organism and populations. A special opportunity exists
distribution of the toxicant within the body; (4) potential for medically trained personnel, both veterinarians and
biotransformation to less, equal or more toxic form; and physicians, to put the expanding knowledge of molecular
(5) the rate of excretion by route (urine, feces, or exhala- and cellular processes into the context of overt disease.
tion). All of these aspects of toxicokinetics may be influ- And vice versa, there is a need for molecular and cellular
enced by species differences in physiological and biologists to become more knowledgeable of disease pro-
biochemical characteristics. Modern approaches to model- cesses. After years of emphasis on a reductionist approach
ing toxicokinetics attempt to take account of both species to basic biomedical science, it has become recognized
differences and similarities in influencing the fate in the that this approach needs to be complemented by an inte-
body of toxicants. It is also important to recognize that grative approach. This has recently been termed “systems
the exposure or dose level may influence the kinetics of biology.” In my view, this is not really a new concept.
a toxicant and its metabolite(s). This is an especially It is more a rediscovery and refinement of the concepts
important consideration in extrapolating from laboratory of integrated biology and pathobiology used in veterinary
studies that may be conducted at high exposures and doses medicine for decades.
to lower more environmentally relevant exposures/doses. There has been great enthusiasm for the use of mecha-
nistic information in safety/risk evaluations as will be dis-
cussed later. Recognition of the difficulty of characterizing
Toxicodynamics
all of the individual mechanistic steps by which
The linkage between dose and adverse health outcome a chemical may cause disease has given rise to the term
shown in Fig. 1.1 involves multiple mechanisms, as vari- “mode of action,” which has been defined as the dominant
ous toxicants may potentially impact all the cells and step(s) involved in producing a given toxic endpoint. An
organ systems of the body. Increasingly, scientists have example is the role of cell killing as the mode of action
attempted to model these relationships that, in parallel for large intakes of chloroform (Butterworth et al., 1995)
to the nomenclature for the kinetic phase, are called or formaldehyde (Conolly et al., 2004) over extended