Pesticide Excretion - Pesticide Biotransformation and Disposition - page 184

Although such routes of excretion are probably only a small proportion of the
total excretion of any particular xenobiotic, they may provide a noninvasive method
of estimating exposure or total body burden. Analysis of bird feathers is useful for the
assessment of heavy-metal exposure, and the amount of cotinine, a major metabolite
of nicotine, in saliva has been used extensively as a biomarker for nicotine uptake. The
excretion of atrazine in saliva has also been tested in rats as a potential biomarker of
exposure in exposed workers ( Lu et al., 1997 ).
CELLULAR ELIMINATION
To prevent concentration at toxic levels, hepatocytes and other cells have active trans-
port processes to eliminate xenobiotics. Because the metabolism of xenobiotics gener-
ally yields products that are more polar and, consequently, have reduced capacity for
passive diffusion compared to the parent compound, such transport processes are essen-
tial for cell viability. Since the publication of the second edition of the Handbook of
Pesticide Toxicology ( Krieger, 2001 ) there has been a dramatic increase in research on the
role of transport proteins, or transporters, and, as a result, in our knowledge of their
importance in the bioprocessing of xenobiotics ( Miller, 2008 ). As yet this knowledge
has not been applied extensively to pesticides; however, some general outlines of the
role of transporters in pesticide bioprocessing are beginning to emerge. Many active-
transport proteins have been sequenced and classified into superfamilies and families. In
mammals, those transporters with xenobiotic-transport functions fall within the ABC
superfamily, a group of ATP-dependent proteins ( Miller, 2008 ). Of particular interest
with regard to pesticides are p -glycoprotein and MRP (multidrug resistance-associated
protein). MRP has the capacity to transport glutathione, sulfate, or glucuronide con-
jugates, whereas p -glycoprotein is known to transport a wide array of xenobiotics,
including some pesticides.
Studies of the role of transporters in pesticide bioprocessing are generally one of
two types. In the first type, the ability of the pesticide to inhibit the efflux of a chemi-
cal known to be transported by the transporter in question is measured, while in the
second type the ability of the pesticide to bind to a particular transporter is measured.
A useful summary of pesticides and transporters is included in Leslie et al. (2005) .
The importance of the role of transporters with regard to pesticides was first illus-
trated by the fact that p -glycoprotein knockout mice died when treated with the
miticide ivermectin, subsequently shown to be due to the accumulation of ivermec-
tin in the brain because of the absence of p -glycoprotein in the blood-brain barrier
( Schinkel et al., 1994 ). This and subsequent studies ( Lanning et al., 1996a,b; Macdonald
and Gledhill, 2007 ) led to the conclusion that p -glycoprotein provided protection
from the toxic effects of both ivermectin and chlorpyrifos. Other pesticides, includ-
ing metolachlor ( Leslie et al., 2001 ), fenitrothion, methoxychlor, and chlorpropham