Appendix B
Pharmacokinetics and Metabolism of Pesticides

Pharmacokinetic data are important in considering the relative risks posed by pesticides to the health of different species of laboratory animals and humans. A basic tenet of toxicology is that toxic effects are a function of the concentration of the bioactive form of a chemical in a target organ. Thus, the degree and duration of a toxic response are dependent on how much of the bioactive moiety reaches its target site and how long it remains there. This is a function of the extent of the chemical’s system absorption, distribution, metabolism, interaction with cellular components, and elimination.

Dermal exposure, inhalation, and ingestion are the primary routes of human exposure to pesticides and other chemicals. The percutaneous absorption of pesticides varies widely, as members of many different chemical classes are used to control unwanted insects, fungi, plants, and animals. The outermost layer of the epidermis, the stratum corneum, serves as the barrier to penetration. The thickness of this layer over different parts of the body varies significantly, as does the extent of systemic absorption. The stratum corneum is composed largely of tightly adhering, cornified epithelial cells impregnated with sebum and sweat. The lipophilic sebum normally predominates, so as a general rule, lipid-soluble compounds are absorbed more readily than hydrophilic compounds. Shah et al. (1987), however, did not find good correlation between octanol-water partition coefficients and dermal absorption of a diverse group of 14 pesticides in rats. Solubilization of pesticides on the skin’s surface greatly aids in their dermal penetration. The EPA usually requires percutaneous absorption studies in rodents as part of the pesticide registration applica-



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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues Appendix B Pharmacokinetics and Metabolism of Pesticides Pharmacokinetic data are important in considering the relative risks posed by pesticides to the health of different species of laboratory animals and humans. A basic tenet of toxicology is that toxic effects are a function of the concentration of the bioactive form of a chemical in a target organ. Thus, the degree and duration of a toxic response are dependent on how much of the bioactive moiety reaches its target site and how long it remains there. This is a function of the extent of the chemical’s system absorption, distribution, metabolism, interaction with cellular components, and elimination. Dermal exposure, inhalation, and ingestion are the primary routes of human exposure to pesticides and other chemicals. The percutaneous absorption of pesticides varies widely, as members of many different chemical classes are used to control unwanted insects, fungi, plants, and animals. The outermost layer of the epidermis, the stratum corneum, serves as the barrier to penetration. The thickness of this layer over different parts of the body varies significantly, as does the extent of systemic absorption. The stratum corneum is composed largely of tightly adhering, cornified epithelial cells impregnated with sebum and sweat. The lipophilic sebum normally predominates, so as a general rule, lipid-soluble compounds are absorbed more readily than hydrophilic compounds. Shah et al. (1987), however, did not find good correlation between octanol-water partition coefficients and dermal absorption of a diverse group of 14 pesticides in rats. Solubilization of pesticides on the skin’s surface greatly aids in their dermal penetration. The EPA usually requires percutaneous absorption studies in rodents as part of the pesticide registration applica-

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues tion process. There are pronounced interspecies differences in the thickness of the stratum corneum, dermal blood flow rate, and other determinants of absorption (Mattie et al., 1994; Monteiro-Riviere et al., 1990). Human skin usually is less permeable than rodent skin to many chemicals (Poet, 2000). Information on the absorption of pesticides and other chemicals from the lungs is often quite limited. Pulmonary exposure is not a major concern for many compounds that have low vapor pressures. Some pesticides, such as soil and grain fumigants, however, are relatively volatile and may be inhaled in high concentrations. Inhaled fumigants such as ethylene dibromide, trichloropropane, and dibromochloropropane are well absorbed and can exert toxic and/or carcinogenic effects in mice and rats. These lipophilic compounds readily diffuse across the respiratory epithelium of the alveoli into the profuse capillary supply of the pulmonary circulation. Systemic absorption of volatile organic chemicals (VOCs) (e.g., trichloroethylene) is often greater in rodents than in humans subjected to equivalent inhalation exposures (Fisher, 2000). The interspecies difference can be attributed to rodents’ higher respiratory rates, cardiac outputs, and blood-air partition coefficients—three major determinants of pulmonary absorption of VOCs (Bruckner and Warren, 2001). The gastrointestinal (GI) tract is the major portal of entry of most pesticide contaminants of food and water. The rapidity and extent of systemic absorption depends on the physical and chemical properties of the compound, as well as conditions within the GI tract. Some of the more important endogenous factors include gastric emptying and intestinal motility; gut flora; acid and enzyme secretory activities; cellular transport systems; blood supply; and mucosal structure and surface area. The small intestine has the greatest surface area and is frequently the optimal absorption site. Systemic absorption of different classes of pesticides varies widely. As a rule, lipid soluble, unionized forms are relatively well absorbed throughout the GI tract. The molecular weight of highly lipophilic compounds such as pyrethroid insecticides (Anadon et al., 1996) can increase to a point that mucosal penetration diminishes. Ingested arsenic, copper, cadmium, and other metals are poorly absorbed by adults. Experiments by Kostial et al. (1978) reveal substantially lower blood levels of lead, mercury, cadmium, and manganese in adult rats than in sucklings given comparable oral doses of the metals. Morphological and functional immaturities of intestinal epithelial cells account for the greater penetrability of the gut of neonatal animals and humans. Once a chemical has entered the bloodstream, it is distributed throughout the body. The initial phase of systemic distribution is governed largely by tissues’ rate of blood perfusion and by the rate at which the compound exits the bloodstream (Rozman and Klaassen, 2001). Cer-

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues tain organs, including the brain and testes, are afforded some degree of protection from polar and/or large molecules by tight capillary cell junctions, enveloping cells and transporters. The immature blood-brain barrier of young animals and children is more permeable than that of adults to metals (e.g., mercury, lead, cadmium) (Kostial et al., 1978). Some pesticides, such as dieldrin and atrazine (McMullin et al., 2003), bind extensively to plasma proteins. As long as the compounds are bound, they are not able to leave the bloodstream and reach sites of action or elimination. Substantial binding thereby generally reduces the maximum activity of chemicals, but can prolong their effects. The final phase of distribution is governed largely by the affinity of a compound or its metabolite(s) for a particular organ or tissue. The liver and kidney have a high capacity for binding a wide variety of xenobiotics. The lungs preferentially bind and accumulate paraquat, which exerts its injurious effects there. Metallothionein, a protein that avidly binds heavy metals, is present in high concentrations in the kidneys. Lipophilic pesticides, such as chlordane, DDT and pyrethroids, accumulate in body fat, from which they are slowly released (Jandacek and Tso, 2001). Biotransformation plays a major role in preventing the accumulation of lipid-soluble xenobiotics in the body. Elimination of such compounds often depends on their conversion by enzyme-catalyzed reactions to more water-soluble forms that can be excreted in the urine and bile. Xenobiotic-metabolizing enzymes tend to have broad, overlapping substrate specificities. Many such enzymes are expressed constitutively (i.e., are synthesized in the absence of an apparent external stimulus), with the synthesis of some induced (i.e., stimulated) by the presence of the chemical they transform. Enzymes frequently exist in multiple forms (i.e., isozymes) with different substrate affinities. Xenobiotic-metabolizing enzymes and their isozymes are distributed widely throughout the body. The preponderance are found in the liver, though certain cell types in different extrahepatic organs exhibit relatively high levels of specific enzymes. There are often considerable interspecies differences in the presence and activity of enzymes and isozymes in particular tissues (Lin, 1995). Biotransformation is a key determinant of the toxicity of many pesticides and other chemicals. Biotransformation results in detoxification and hastened elimination of some pesticides. The parent compound, for example, is responsible for the neurotoxic action of pyrethroids. These compounds are inactivated by the concerted actions of carboxylesterases and P450s-catalyzed hydroxylation and subsequent conjugation (Soderlund et al., 2002). Organophosphates are also detoxified by esterase-catalyzed hydrolysis, although desulfuration by P450s produces oxons, the neurotoxic moieties that bind to and inhibit acetylcholinesterase (Sultatos, 1994). The pronounced acute toxicity of chlorpyrifos in immature rats is attrib-

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues uted to their deficiencies of chloropyrifos-oxonase (i.e., the A-esterase that hydrolyzes the oxon) (Mortensen et al., 1996) and of carboxylesterase (Moser et al., 1998). Thus, recognition of metabolic differences is essential to understanding variances in the toxicity of xenobiotics in different cells, tissues, species, strains, sexes, races, and age groups. Toxicants and their metabolites are eliminated from the body by several routes. Many xenobiotics, as described above, are converted to more water-soluble products, so that they may be discharged in the largely aqueous urine and bile. Renal excretion is the principal pathway for elimination of these compounds (Rozman and Klaassen, 2001). Biliary excretion also can play a major role for some parent compounds and metabolites, notably conjugates formed in Phase II reactions. The relative contribution of urinary and biliary excretion, and the extent of enterohepatic recirculation, are compound and species specific (Lin et al., 1995). Volatile parent compounds and metabolites can be exhaled, but this route of elimination is not important for most pesticides. Hair, fingernails, desquamated skin, and body secretions (e.g., milk, tears, saliva, and sweat) have limited capacity to eliminate chemicals. REFERENCES Anadon, A., M. R. Martinez-Larranaga, M. L. Fernandez-Cruz, M. J. Diaz, M. C. Fernandez, and M. A. Martinez. 1996. Toxicokinetics of deltamethrin and its 4'-HO-metabolite in the rat. Toxicology and Applied Pharmacology 141:8-16. Bruckner, J., and D. A. Warren. 2001. Toxic effects of solvents and vapors. In: Klaassen, C., ed. Casarett and Doull’s Toxicology: The Basic Science of Poisons. 6th ed. New York: McGraw-Hill. Fisher, J. W. 2000. Physiologically based pharmacokinetic models of trichloroethylene and its oxidative metabolites. Environmental Health Perspective 108(Suppl. 2):265-273. Jandacek, R. J., and P. Tso. 2001. Factors affecting the storage and excretion of toxic lipophilic xenobiotics. Lipids 36:1289-1305. Kostial, K., D. Kello, S. Jugo, I. Rabar, and T. Maljkovic. 1978. Influence of age on metal metabolism and toxicity. Environmental Health Perspectives 25:81-86. Lin, J. H. 1995. Species similarities and differences in pharmacokinetics. Drug Metabolism and Disposition 23:1008-1020. Mattie, D. R., J. H. Grabau, and J. N. McDougal. 1994. Significance of the dermal route of exposure to risk assessment. Risk Analysis 14:277-284. McMullin, T. S., J. M. Brzezicki, B. K. Cranmer, J. D. Tessari, and M. E. Andersen. 2003. Pharmacokinetic modeling of disposition and time course studies with carbon 14 atrazine. Journal of Toxicology and Environmental Health 66:941-964. Monteiro-Riviere, N. A., D. G. Bristol, T. O. Manning, R. A. Rogers, and J. E. Riviere. 1990. Interspecies and interregional analysis of the comparative histological thickness and laser doppler blood flow measurements at five cutaneous sites in nine species. Journal of Investigative Dermatology 95:582-586. Mortensen, S. R., S. M. Chanda, M. J. Hooper, and S. Padilla. 1996. Maturational differences in chlorpyrifos-oxonase activity may contribute to age related sensitivity to chlorpyrifos. Toxicology Science 11:279-287.

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Intentional Human Dosing Studies for EPA Regulatory Purposes: Scientific and Ethical Issues Moser, V. C., S. M. Chanda, S. R. Mortensen, and S. Padilla. 1998. Age and gender related differences in sensitivity to chlorpyrifos in the rat reflect developmental profiles of esterase activities. Toxicology Science 46:211-222. Poet, J. S. 2000. Assessing dermal absorption. Toxicology Science 58:1-2. Rozman, K. K., and C. D. Klaassen. 2001. Absorption, distribution, and excretion of toxicants. In: Klaassen, C., ed. Casarett and Doull’s Toxicology: The Basic Science of Poison. 6th ed. New York: McGraw-Hill. Shah, P. V., H. L. Fisher, M. R. Sumler, R. J. Monroe, N. Chernoff, and L. L. Hall. 1987. Comparison of the penetration of pesticides through the skin of young and adult rats. Journal of Toxicology and Environmental Health 21:353-366. Soderlund, D. M., J. M. Clark, L. P. Sheets, L. S. Mullin, V. J. Piccirillo, D. Sargent, J. T. Stevens, and M. L. Weiner. 2002. Mechanisms of pyrethriod neurotoxicity: implications for cumulative risk assessment. Toxicology 171:3-59. Sultatos, L. G. 1994. Mammalian toxicology of organophosphorus pesticides. Journal of Toxicology and Environmental Health 43:271-289.