CHAPTER

Introduction to Pesticide
Biotransformation and Disposition
Ernest Hodgson

North Carolina State University, Raleigh, NC, USA

Outline
Introduction
Relevance of Biotransformation and Disposition Studies
References

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3

INTRODUCTION
It should be emphasized that, although pesticides and their use have many positive
attributes, they are toxicants and, in terms of their interactions with living organisms,
are xenobiotics, and are processed in the same way as other xenobiotics such as clinical
drugs and industrial chemicals.
It should also be emphasized that their toxicity is not due to a single defining
molecular event or interaction, but rather a cascade of events beginning with exposure and culminating with the expression of one or more toxic endpoints. This cascade
(Figure 1.1) includes adsorption, distribution, metabolism (both detoxication and activation), distribution of metabolites, interaction with cellular macromolecules (such as
RNA, DNA, and proteins), repair, and excretion. The processes involved may be reversible to a greater or lesser extent, they may include alternative pathways, and they may
be modified by chemical and physiological interactions. Thus, exposure to a toxicant
does not inevitably lead to a toxic endpoint; metabolism, excretion, or repair may render the original exposure without effect (Hodgson, 2010a). Finally, these processes and
the genes, enzymes, transporters, receptors, etc., involved are all subject to considerable
variation with cell type, organ, individual, species, and strain.
The aspects covered in this volume include adsorption, distribution, biotransformation
(metabolism), and excretion and are collectively known as disposition. Biotransformation
(metabolism), a more specialized term and a subdivision of disposition, of a xenobiotic is
the total of all of the chemical transformations of that xenobiotic taking place in a living
organism. In the case of xenobiotics (including pesticides), the use of the term disposition
is often preferred to metabolism, since the latter is most often used to describe the total of

Pesticide Biotransformation and Disposition

DOI: 10.1016/B978-0-12-385481-0.00001-0

2012 Elsevier Inc.

All rights reserved.

Ernest Hodgson

Exposure and absorption at portals of entry

Distribution to organs and tissues

Metabolism to more
toxic metabolites

Metabolism to less
toxic metabolites

Excretion

Metabolism to
conjugation products

Redistribution to organs and tissues

Interaction with macromolecules
(Protein, DNA, RNA, Receptors, etc.)

Turnover and repair

Toxic effects
Genetic, Carcinogenic, Reproductive, Neurotoxic, etc.

Figure 1.1 Chemical toxicity: a cascade of events.

all chemical reactions of normal body constituents. However, the two terms can usually
be used as synonyms without confusion.

RELEVANCE OF BIOTRANSFORMATION AND DISPOSITION STUDIES

Studies of pesticide disposition, particularly biotransformation, are critical to the
understanding of the toxic mode of action in both target and nontarget organisms.
Biotransformation may result in the formation of less toxic (detoxication) and/or more
toxic (activation) products, while the various other processes shown in Figure 1.1 may
determine the balance between toxic and nontoxic events. While disposition in nontarget species, including humans, is the primary focus of this volume, studies in target
species facilitate the development of more effective, safer pesticides.
Most important, disposition studies facilitate risk analysis. They make possible phy
siologically based pharmacokinetic studies, since not only is knowledge of the uptake,
distribution, and rate of excretion of the parent chemical necessary, but also that of
the distribution and excretion of its metabolites. Mechanism of action at the molecular level cannot be defined unless all active metabolites have been identified and their
interactions at the site of action determined. Quantitative structure activity relationship
studies, important for the prediction of both effectiveness and toxicity, likewise depend
on detailed knowledge of metabolites and their formation.

Introduction to Pesticide Biotransformation and Disposition

Since risk analysis of pesticides relies heavily on studies of single chemicals in surrogate animals, studies of pesticide metabolism in humans assume particular importance.
Given the ready availability of hepatocytes, cell fractions, cell lines, and recombinant
enzymes, all derived from humans, ethical human studies have been relatively easy to
conduct for the past decade.
The surrogate animals used in metabolism studies, generally rodents, are highly
inbred, while the human population is outbred and pesticides are, more often than not,
used in mixtures or in temporal proximity so close as to have the same implications
for risk analysis as mixtures. Thus studies in humans are essential if variation is part of
the risk assessment paradigm and if subpopulations and individuals at increased risk
are to be identified. They are also important in defining interactions between pesticides in mixtures and between pesticides and endogenous metabolites that may impact
human health. Moreover, if surrogate animals are to be used, some studies in humans
may indicate which experimental animal is the best surrogate for humans for studies of
a particular pesticide or mixture of pesticides.
Given the emerging changes in risk assessment (National Research Council, 2007;
Hodgson, 2010b; Kullman et al., 2010) that rely heavily on human cell lines and the
techniques of genomics, proteomics, metabolomics, and informatics, the nature of
human studies will doubtless change but their importance will increase.

REFERENCES
Committee on Toxicity Testing and Assessment of Environmental Agents, National Research Council. (2007).
Toxicity testing in the 21st century: A vision and a strategy. Washington, DC: National Academies Press.
Hodgson, E. (2010a). Introduction to toxicology. In E. Hodgson (Ed.), A textbook of modern toxicology
(4th ed.). Hoboken, NJ: John Wiley & Sons (Chap. 1).
Hodgson, E. (2010b). Future considerations. In E. Hodgson (Ed.), A textbook of modern toxicology (4th ed.).
Hoboken, NJ: John Wiley & Sons (Chap. 29).
Kullman, S. W., Mattingly, C. J., Meyer, J. N., & Whitehead, A. (2010). Perspectives on informatics in toxicology. In E. Hodgson (Ed.), A textbook of modern toxicology (4th ed.). Hoboken, NJ: John Wiley & Sons
(Chap. 28).