Page 729 - The Toxicology of Fishes

Biomarkers 709

rhythms (Campbell et al., 2002) and adjustment of ion flux rates with social status (Sloman et al., 2002).
Behavioral biomarkers may therefore be usefully applied and integrated with other physiological mea-
surements to give an overall picture of biological effect at the whole organism level.

Pathological Biomarkers
Sublethal exposure to environmental chemicals may result in changes in the histological structure of
cells and the occurrence of pathologies which can significantly modify the function of tissues and organs.
Use of histopathological techniques in a biomarker approach has the advantage of allowing investigators
the opportunity to examine specific target organs and cells as they are affected by exposure to environ-
mental chemicals. Additionally, histopathology provides a means of detecting both acute and chronic
adverse effects of exposure in the tissues and organs of individual organisms. Cells are the component
units of organization in each tissue, and they show a variety of structural and functional specializations,
based on the quantitative differences in individual organelles. Cellular organelles may be considered
highly conserved structures, as they are recognizable in finfish as well as shellfish. Hinton (1994)
suggested it is the conservative nature or common features of cellular organization in vertebrate and
invertebrate organisms that make histopathological examination a valuable tool in the biomarker
approach. Use of molecular responses within aquatic organisms in the biomarker approach has been
reviewed, and it was noted that such responses occur early and are typically the first detectable quanti-
fiable response to exposure to environmental chemicals. Linkage of molecular events to damage at the
cell and higher levels of biological organization is only beginning to emerge, and greater effort is being
directed toward determining the significance of molecular events to subsequent forms of cellular injury
and response (Au, 2004; Myers and Fournie, 2002). Hinton et al. (1992) suggested the integration of
histopathology with biochemical and physiological biomarker approaches, as histopathological alter-
ations are the net result of adverse biochemical and physiological changes in an organism. Because
genes control cell products and therefore appearance of specific cells, it is apparent that a focus on cells
would enhance the ability to detect common mechanisms of action. Histopathological biomarkers are
considered higher level biological responses and often signify prior metabolism and macromolecular
binding. Most chemicals that are potentially genotoxic require metabolic activation to an ultimate form
that binds covalently, forming adducts to DNA. If the adduct is not repaired and persists, subsequent
changes lead to a multistep process that could result in cell death or perhaps abnormal growth and tumor
formation (Figure 16.6). In the latter case, the histopathologic biomarker is a higher level response
following chemical and cellular interaction. Similarly, exposure to an environmental chemical may induce
the activity of a specific enzyme or enzyme isoform. Subsequent exposure could lead to increased
metabolism by the induced enzyme, resulting in levels of toxic intermediates that exceed cellular
detoxification mechanisms; therefore, induction and metabolism could lead to cellular toxicity and death,
subsequently detected as tissue necrosis or apoptosis.

Morphological Abnormalities
The view that disturbances in structure or function of individual cells form the basis of a disease state
or, in this case, toxicity was first put forward in the 19th century with the concept of “cellular pathology”
suggested by Rudolf Virchow, known as the father of pathology (Cotran et al., 1994). Pathology has
been an indispensable and robust technique in established routine toxicology studies in rodents, per-
formed for the purpose of risk assessment. Its value lies not only in the sensitivity with respect to
establishing thresholds of toxicity but particularly in the identification of target organs and mechanisms
of action. In aquatic toxicology, the use of the histopathologic approaches in evaluating toxicologic
pathology of organisms has been shown to have a number of strengths.
The documentation of neoplasms in aquatic organisms was perhaps the first use of histopathological
indices in the biomarker approach to environmental monitoring and began as early as the 1800s with
the description of tumors in fish and mollusks. By the 1960s, several epizootic neoplasms had been
reported in feral fish. The connection between epizootic neoplasms in feral fish and the chemical