Biological Function of Xenobiotics through Protein Binding and Transportation in Living Cells
Abd El-Moneim M.R. Afify
The main objective of this study is to find out how xenobiotics (especially pesticides) bind to special protein and transported through the main living cell to reach its targeting. Because pesticides residues exists in foods, water, plants and underground then transported to human through the above sources, a lot of disease were detected in high intensity in the population in different countries. Therefore, research carried out to find out relationship between pesticides contamination in human breast milk and animal serum and protein profiles. Pollution with xenobiotics induce different form of cytochrome P-450 in human liver and directly accelerate the rate of α-synuclein fibril formation in living cell. Therefore, our investigation concern to find out the relationship between xenobiotics and protein binding and transportation in living cell. Breast milk and rat serum proteins as well as fish were used as examples of pollution materials with xenobiotics to find out the above relation.
February 05, 2010; Accepted: April 21, 2010;
Published: June 16, 2010
To fulfill and find out the relationship between xenobiotics and proteins involved during transportation in living cell , we start first to define xenobiotics and transport proteins and the possibility xenobiotic-protein Interactions in living cell.
Definition of Xenobiotic
A xenobiotic is a chemical which is found in an organism but which is not
normally produced or expected to be present in it. It can also cover substances
which are present in much higher concentrations than are usual. Specifically,
drugs such as antibiotics are xenobiotics in humans because the human body does
not produce them itself, nor are they part of a normal diet. Natural compounds
can also become xenobiotics if they are taken up by another organism, such as
the uptake of natural human hormones by fish found downstream of sewage treatment
plant outfalls, or the chemical defences produced by some organisms as protection
against predators. However, the term xenobiotic is very often used in the context
of pollutants such as dioxins and polychlorinated biphenyls and their effect
on the biometabolism, because xenobiotics are understood as substances foreign
to an entire biological system, i.e., artificial substances, which did not exist
in nature before their synthesis by humans.
Xenobiotics in the Environment
Xenobiotics substances are becoming an increasingly large problem in sewage
treatment systems, since they are relatively new substances and are very difficult
to categorize. Antibiotics, for example, were derived from plants originally
and so mimic naturally occurring substances. This, along with the natural monopoly
nature of municipal waste water treatment plants makes it nearly impossible
to remove this new pollutant load. Some xenobiotics are resistant to degradation
,for example, they may be synthetic organochlorides such as plastics and pesticides,
or naturally occurring organic chemicals such as polyaromatic hydrocarbons (PAHs)
and some fractions of crude oil and coal. However, it is believed that microorganisms
are capable of degrading all the different complex and resistant xenobiotics
found on the earth.
Both the beneficial and harmful effects of xenobiotics are determined by
xenobiotic-protein interactions or how xenobiotic and living cell organisms
react to each other. To do its job, a xenobiotic must: 1) penetrate the organism,
2) move or be transported to the site of action and 3) there disrupt or alter
the vital function.
Protein Involved During Xenobiotics Transportation
Membrane transport protein (or simply transporter) is a protein involved
in the movement of ions, small molecules, or macromolecules, such as another
protein across a biological membrane. Transport proteins are integral membrane
proteins; that is they exist within and span the membrane across which they
transport substances. The proteins may assist in the movement of substances
by facilitated diffusion protein or active transport. The mechanism of action
of these proteins is known as carrier-mediated transport. There are two forms
of carrier-mediated transport, active transport and facilitated diffusion (Crompton,
Facilitated diffusion Protein speeds the movement of a chemical through a membrane in the absence of energy input; therefore, the transported chemical can move only down a concentration gradient. This can be accomplished by the formation of a high-specificity pore or channel that spans the membrane. These polar "holes" through the membrane are lined by specific amino acids residues that lower the energy barrier to the movement of polar molecules (Fig. 1).
Now we will deal with some specific proteins involved in binding with xenobiotic especially pesticides and transportation of its for targeting and function of xenobiotic.
|| Transportation of xenobiotics by facilitated diffusion protein
Identification of an Inducible Form of Cytochrome P-450 in Human Liver
The cytochromes P-450 are a family of hemoproteins, abundant in the endoplasmic
reticulum of the hepatocyte, that catalyze the oxidative metabolism of many
drugs, environmental chemicals and endogenous compounds (Watkins
et al., 1985, Popper et al., 1979).
An important characteristic of some of the forms of cytochrome P-450 is that
they are inducible. For example, different forms of liver cytochrome P-450 accumulate
in rats treated by a member of one of three classes of inducers (Guengerich
et al., 1982) typified, respectively, by phenobarbital (P-450b, P-450e),
3-methylcholanthrene (P-450c, P-450d) and pregnenolone-16a-carbonitrile (PCN)
(P-450p). Since, the amounts and types of cytochromes P-450 in the liver may
be rate-limiting for metabolism of foreign chemicals, enzyme induction may play
an important role in such clinically relevant phenomena as interactions among
therapeutic drugs, Mayer et al., 1980) metabolic
idiosyncrasy in hepatotoxic drug reactions (Davies, 1981)
and inter individual differences in susceptibility to toxic effects of environmental
chemicals ( Kouri et al., 1982). There is abundant,
albeit indirect, evidence that human liver also contains cytochromes P-450 that
are inducible. For example, exposure of humans to inducers of animal cytochromes
P-450 including such drugs as phenobarbital (Kellermann
and Luyten-Kellermann, 1977), macrolide antibiotics (Ohnhaus
and Park, 1979; Ohnhaus et al., 1983), or
environmental chemicals such as organochlorine pesticides (Kolmodin-Hedman,
1974) or polychlorinated biphenyls (Alvares et al.,
1977), accelerates the disappearance of administered substrates for the
cytochromes P-450 from the blood or the appearance of metabolites of such model
drugs in the breath (Henry et al., 1979). Such
patients may also exhibit increased urinary excretion of metabolites of endogenous
substrates such as 6,8-hydroxy derivatives of cortisol (Saenger
et al., 1981). Additional evidence for liver enzyme induction in
humans are proliferation of the smooth endoplasmic reticulum in hepatocytes,
as judged by electron microscopic examination of liver biopsies (Pamperl
et al., 1984), increased urinary excretion of glucaric acid (a breakdown
product of a constituent of the endoplasmic reticulum) (Hunter
et al., 1971) and increased concentration of CO-binding hemoprotein
or drug oxidizing activities in liver microsomes prepared from such patients
(Schoene et al., 1972). However, although it
has been possible to purify at least six individual polypeptide forms of human
liver cytochrome P-450 (Wang et al., 1983), there
has to date been no clear evidence which, if any, of these cytochromes are inducible.
Interactions of Pesticides with the Estrogen-binding Protein in Rat
The binding of 3H-estradiol to testicular cytosol was inhibited by o,p-DDT,
a DDT analog which is estrogenic in the intact female, but not by p,p-DDE which
is a nonestrogen in the female. The pesticide methoxychlor, which is estrogenic
in vivo in the female, failed to inhibit 3H-estradiol binding, presumably requiring
metabolic activation for binding to the testicular cytosol. In fact, its di-demethylated
metabolite 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane (HPTE), also estrogenic
in vivo, caused marked suppression of 3H-estradiol binding (Bulger
et al., 1978). Bulger et al. (1981) stated
that by using Laboratory grade methoxychlor (99% pure), base-washed methoxychlor
and a metabolite of methoxychlor, 2,2-bis(p-hydroxyphenyl)-1,1,1-trichloroethane
(HPTE), were tested for their ability to compete with [3 H] estradiol-17 beta
([3 H]E2) for specific binding to the estrogen receptor from immature rat uterine
cytosol. The effect of o,p-DDT on the binding of 3H-estradiol to DMBA-induced
rat mammary tumor cytosolic estrogen-binding protein (EBP) was examined in vitro.
Scatchard plot analysis indicated that o,p'-DDT displaced estradiol from specific
4S and 8S proteins. As estrogens have been shown to affect the development and
growth of these tumors, this experimental findings suggest that o,p-DDT may
possibly influence DMBA-induced tumors in an estrogenic manner (Mason
and Schulte, 1983).
Isolation of Pesticide-Binding Protein from Rat Blood
Rats were given a single oral dose of the herbicide propachlor-[1-14C]
(8x106 d.p.m., 10.3 mg). The plasma, erythrocyte cytosol and erythrocyte
ghosts (collected 90 min after dosing) contained 41, 15 and 28%, respectively,
of the 14C in the blood (0.5% of the 14C dose). Plasma,
erythrocyte cytosol and erythrocyte ghost were found to contain protein(s) 13.4
to 13.9 kDa (MW) which were associated with the 14C (2.4% of 14C
in plasma; 51% of 14C in erythrocyte cytosol and 65% of 14C
in erythrocyte ghosts). This 14C associated with protein was extractable
with methanol and was tentatively characterized by T.L.C. to be the cysteine
conjugate (11%), the mercapturic acid conjugate (18%), S-oxide of the
mercapturic acid conjugate (18%) and propachlor (25%). MW of the native 13.4-13.9
kDa protein(s) was found to be 43.5 kDa. Immunoblot or binding studies of the
13.4-13.9 kDa protein(s) showed no evidence that this protein(s) was liver or
heart fatty-acid-binding-protein (FABP) or transthyretin (Larsen
et al., 1994).
Transportation of Pesticides in Fish
A number of reports have appeared on the toxicity, uptake and tissue distribution
of pesticides in a number of fishes (Guiney and Peterson,
1980; Kouudinya and Ramamurthi, 1979) studied the
effect of Sevin on some hematological parameters in Sarotherodon mossambicus.
Vijayalakshimi (1980) observed that sumithion reduced
tissue respiration and oxygen consumption of the fish, Etroplus maculatus.
Some amount of pesticides can enter the digestive system of fishes through
the consumption of food chain organisms and pesticides present in water and
in food material can adversely affect the processes of digestion of food material
and absorption of nutrients by the intestine (Jarvinen and
Tyo, 1978; Mac et al., 1979; Neimi
and Cho, 1980). It is possible that pesticides entering the intestine of
fishes either through water or food can reduce the rate of transport of nutrients.
Among the three nutrients examined, the decrease in the rate of transport was
maximum in case of tryptophan and the rate of uptake of fructose was more affected
than that of glucose. The present study also shows that higher concentrations
of Sevin decreased the rate of transport of the three nutrients to a greater
extent than lower concentrations. Sastry and Siddiqui (
1982) and Sastry and Sharma (1978) have also reported
similar decrease in the rate of intestinal transport of glucose in Channapunctatus
by endosulfan and quinalphos. Madge (1976) studied
the absorption of amino acid and hexoses in mice treated with hexachlorobiphenyls
and noted decrease in the transport rate. The decrease was attributed to either
a carrier effect at the brush border membrane or impairment of cellular metabolism.
Pesticides Directly Accelerate the Rate of α-Synuclein Fibril Formation
Parkinson's disease involves intracellular deposits of α-synuclein
in the form of Lewy bodies and Lewy neurites. The etiology of the disease is
unknown, however, several epidemiological studies have implicated environmental
factors, especially pesticides. Here we show that several pesticides, including
rotenone, dieldrin and paraquat, induce a conformational change in α-synuclein
and significantly accelerate the rate of formation of - α synuclein fibrils
in vitro. They propose that the relatively hydrophobic pesticides preferentially
bind to a partially folded intermediate conformation of α -synuclein, accounting
for the observed conformational changes and leading to association and subsequent
fibrillation. These observations suggest one possible underlying molecular basis
for Parkinsons disease. α-Synuclein, a relatively abundant brain protein
of 140 amino acids and of unknown function, was first identified in association
with synaptic vesicles (Maroteaux et al., 1988).
α-Synuclein belongs to the class of proteins known as natively unfolded;
i.e., the purified protein at neutral pH is substantially disordered (Uversky
et al., 2001a). Fibrils of α -synuclein have been reported in
Lewy bodies from individuals with Lewy body diseases, as well as in vitro
(El-Agnaf et al., 1998; Narhi
et al., 1999). We have recently established that the fibrillation
of α-synuclein involves a critical partially folded intermediate (Uversky
et al., 2001b). Here, we show that certain pesticides can significantly
stimulate the formation of α-synuclein fibrils. Since, these agents also
induce a conformational change in α-synuclein, that this partially folded
conformation is a critical precursor to association and fibrillation.
In vitro Binding of Trichlorphenol, Fenvalerate and α-Endosulphan to Rat Serum Transferrin and Albumin for Biomonitoring of Pesticides Pollution
||Objectives: To study the changes in serum protein binding
profile with pesticides and remarks any new protein bands after pesticides
incubation in-vitro with rat serum as well as with individual proteins of
transferrin and albumin. Animals Male albino rats obtained from animal house
colony in Faculty of Agriculture (Afify et al.,
||Setting: Biochemistry Department, Faculty of Agriculture,
Cairo University, Cairo, Egypt
||Main outcome measures: Serum transferrin, albumin,
prealbumin and small molecular weight proteins
||Results: Electrophoretic separation of the protein
subunits of rat serum treated with different pesticides showed that these
pesticides have high affinity to transferring, albumin as well as high molecular
weight proteins. The increase in the intensity of transferrin was occurred
with trichlorophenol and α-endosulphan. On the other hand, the intensity
of the albumin fraction was decreased with fenvalerate, while it is markedly
increased with trichlorophenol and α-endosulphan. The individual incubation
of each pesticide with transferrin,, albumin or prealbumin showed that trichlorophenol
and α -endosulphan was found to cause aggregation of transferring by
49.l and 43.9%, respectively, while fenvalerate was found to cause marked
disintegration of transferrin as compared to controls. The albumin fraction
was significantly decreased with the three pesticides. The Pre-albumin was
found to Markedly increased in its Intensity by 44.8 and 57.3% with Trichlorophenol
(5 ppm) and α-endosulphan (15 ppm), respectively
||Conclusion: The results of the current study indicated
that several protein bands have responded to pesticides treatment including
the known serum proteins, transferrin, albumin, prealbumin and small molecular
weigh proteins. However, some of the small molecular weights proteins have
been identified as results of pesticides binding which require further characterization.
Therefore, the detection of serum proteins after electrophoresis is considered
a very good diagnostic parameter for biomonitoring of pesticides pollution
studies (Saleh et al., 1996b; Afify et al.,
Table 1 showed that scanning of electrophoretic profiles
of rat serum incubated with different concentration of pesticides 5, 10, 15
and 20 ppm with trichlorophenol, fenvalerate and α-endosulphan.
Table 2 showed that scanning of electrophoretic profiles of Transferring and albumin incubated with different concentration of pesticides 5, 10 and 15 ppm.
||Scanning electrophoretic pattern of rat serum protein subunits
treated with trichlorophenol, fenvalerate and α-endosulphan pesticides
||Percentage of transferrin and albumin and their protein profiles
after incubation with trichlorophenol, fenvalerate and α-endosulphan
The aim of the present investigation was to determine if there is any changes
among serum proteins which could be used as a biomarker for pesticides pollution.
In addition, during the transport of the pesticides with carrier proteins in
blood throughout the organs, do complex cause a destruction in macromolecules.
The data of the present study revealed that the incubated pesticides have, high
affinity to the proteins binding sites (Saleh et al.,
1996b; Afify et al., 2000). Similar, observations
have been recorded for particle mediated uptake of chlorinated pesticides by
human, rat and insect lipoprotein (Shalsky and Guthrie,
1975; Larsen et al., 1994; Shu
and Nichols, 1979; Maliwal and Guthrie, 1982) and
by serum albumin and α-globulin in rat and rabbit (Shakoori
et al., 1996; Moss and Hathway, 1964). The
binding of pesticides to proteins is correlated to the binding of DNA. DNA was
considered the most important leader of the genetic code in human (Hemminki,
1986) which may induce genetic, risks (Ehrenberg et
al., 1974). Therefore, the binding of pesticides to the macromolecules
of rat serum protein could be serve as biomarker in the monitoring of pesticides
(Hemminki, 1986). Pahler et al.
(1999) showed that the accumulation of some proteins such as alpha 2 macro-globulin
has been implicated in the tumorigenicity of many nongenotoxic chemicals to
the kidney of the male rat. These chemicals have been shown to bind to alpha
2 macro-globulin and this binding was found to impair the renal degradation
of the protein, resulting in lysosomal overload, cell death, increased cell
proliferation and, presumably renal tumor formation. The present study proved
that the major proteins transferrin and albumin are the main sites for the three
studied pesticides. The data of incubation of the three pesticides with transferrin
and albumin were showed that the destruction of transferrin and albumin with
the three pesticides produced a similar but not identical protein profile and
the prealbumin was found to represent the major one as recorded by Altland
et al. (1981). Dissociation into small MW proteins has been demonstrated
in case of in vitro incubation with the tested pesticides. These results
are in agreement with the results obtained by prolonged exposure of proteins
to pesticides (Nilsson et al., 1975). The changes
in the binding of serum acute phase proteins such as transferrin and albumin
with some chemicals has been used to detect or identify human breast cancer
(Heys et al., 1998). Insecticides have been shown
to bind to blood protein especially organochlorine compounds which are extensively
bound to blood lipoproteins (Shalsky and Guthrie, 1975,
1977). Dutta et al. (1992)
revealed that malathion an organophosphorus pesticide has profound effect on
serum protein as other parameters. Therefore, the detection of the prealbumin
as well as small MW proteins after electrophoresis is considered a very good
diagnostic marker for pesticide pollution. In conclusion the induced destructed
proteins by pesticides in-vivo and in vitro may be utilized as biomarkers
reliable for pesticides monitoring (Saleh et al.,
1996b; Afify et al., 2000).
Breast Milk as a Biomarker for Monitoring Human Exposure to Environmental
Pollutants (this work was funded by EPA Grand # CR 818220-02-5 )
Saleh et al. (1996a) cited that 60 million
Egyptian inhabitants can be grouped into three main different community types.
The urban population, living in the capital city of Cairo (15 million) and other
big cities, is generally exposed to air pollutants, especially lead evolving
with vehicle exhaust, petroleum and gasoline vapors, carbon monoxide and mineral
dusts. In addition, the urban communities may also be exposed to toxic residues
in food and drinking water which may include pesticides and other toxicants.
The second large community consists of those living in rural villages who are
more likely to be exposed to pesticides and other agrochemicals. The third community
includes those living in remote desert and mountain areas in the western and
eastern deserts, the Sinai peninsula and northern and eastern sea coasts. The
population in these areas is still engaged in few agricultural activities. There
are also some Bedouin tribes in the southern part of Egypt such as Bassharia
who live mainly on raising herds of camels and sheep in the desert areas. In
such locations, the exposure to man made chemicals and pollutants is a minimum.
Therefore, it is reasonable to consider such inhabitants as a real unexposed
reference group compared to the urban or rural communities. This Egyptian model
structure, where clear differentiation can be drawn between rural, urban and
remote desert inhabitants, is expected to be successful in reaching significant
correlations between typed of human activities and levels of exposure to hazardous
chemicals. Since most organochlorine insecticides are environmentally persistent
and fat soluble, they may accumulate in food and be stored in high concentrations
in tissues and lipid rich organs such as the adipose tissues, liver, meat and
milk (Hernandez et al., 1993). Human milk is
the most important and indispensable food for the newborn. During lactation,
fat mobilization could take place from the adipose tissue and therefore, organochlorine
compounds such as DDT and HCHs and their metabolites are mobilized and released
mainly by breast milk.
Recent epidemiological studies indicated the commonly occurring persistent
pesticides and industrial chemicals found in breast milk. These chemicals are
dichlorodiphenyl trichloroethane as dichlorodiphenyl dichloroethene dieldrin,
chlordane as oxychlordane, heptachlor, polychlorinated biphenyls, polychlorinated
dibenzofurans and polychlorinated dibenzodioxins. We present a worked example
of the kinds of pharmacokinetic assumptions and calculations necessary for setting
regulatory limits of contaminants in the food supply, calculating dose of chemical
contaminants to the nursed infant, converting risks from lifetime exposure in
laboratory animals to risks for short-term exposure in humans and estimating
the excess cancer risk to the nursed infan (Rogan and Ragan,
1994). Thus, monitoring of such residues in mother's milk will be a good
Criterion to measure their impact on general population, not only on the existing
population, but also on the next generation of the newly born children. In Egypt,
a few surveys have been carried out in this regard mainly in two governorates
Beny Sweif and Fayoum. Although the environmental contamination by chlorinated
hydrocarbon insecticides has been reduced since 1970, when these pesticides
were banned, some amounts of these chemicals were recently found in human breast
milk. However, these amounts were within the range of acceptable daily intakes
according to the FAO/WHO guidelines (Dogheim et al.,
1991). On the same time contamination of buffalo milk with pesticides residues
of diazinone insecticide after spraying animals were conducted and results detected
high level in the first day after spraying (0.586 ppm) as reported by El-Kholy
et al. ( 2000). The main objectives of this research was to evaluate
the Egyptian mother's milk contents of organochrlorine insecticides and the
heavy metal lead (Pb) as criterion for measuring the body burden with environmental
pollutants due to long term exposure.
Lead Concentration in Mother's Milk and its Hazardous Impact
Table 3 presents the mean lead concentrations in milks
samples collected from the 20 different locations. According to the daily permissible
level established by the WHO (Vahter and Slorach, 1990)
(5.0 μg kg-1 body weight/day, which is equivalent to about 15.5
ppb in mother's milk), it can be seen that the mean values of lead levels were
below the permissible level in the governorates of Fayoum, Matruh, Minia and
Suez, Lead levels in Aswan. Beheira, Beny Sweif, Dakahlia, Gharbia Giza, Ismailia,
Kaliobia, Menoufia, New Valley North-Sinai, sfarkia and Sohag were slightly
higher than the WHO permissible value. Mean read revels in mother's-milk Alexandria,
Assiut and Cairo were significantly higher than the permissible value. The higher
levels of lead mothers milk from Cairo, Alexandria and Assiut may be attributed
to heavy automobile traffic and the use of leaded gasoline in addition to contamination
of drinking water from the lead drinking pipe lines. There is very little information
regarding the transfer of lead via the milk from mothers who are at high risk,
such as those living in big cities i.e Cairo, Arexandria and Assiut. Chronic
adult exposure to lead occur mainly through the inhalation of dust and fumes
and incidental ingestion of polluted food and drink and the inhalation of cigarette
smoke. The threshold limit value-time weighted average (TLV-TWA) for lead, dust
and fumes is 0.15 mg m-3. An average of 66 μg L-1
mother milk from women in Cairo equivalent to 10.54 μg/kg/day while a child
weighing 5.5 kg may receive at least 58 ìg of lead per day. According
to Mahaffei (1977), the tolerable or maximum daily intake
lead from all sources for infants between birth and the age of 6 months should
be as low as possible and should be less than 100 ìg/day. In Table
4 the lead levels in human milk recorded in this study were compared with
those of other countries from 1971-1994. By comparison with the published data
from other countries, the lead levels in Egypt are between moderate lead levels
found in Japan, Germany, Sweden and the united states and the high value found
in Mexico, Indonesia and Thailand. The current lead level in Egypt, although
higher in some cases than the recommended WHO levels still appears not to be
at the level of a serious risk except in those cases where the lead level is
higher than 100 ppb in Assiut, followed by Cairo and Alexandria.
|| Lead concentration (μg L-1) in Human's Breast
Milk from Egypt
|Error % are shown in parenthesis
Chlorinated Insecticides Levels in Human Milk
The data in Table 5 shows that the main detected organochlorine
insecticides and their metabolites were DDE and lindane. DDT and endosulfan
I residues were also detected in some samples. Endrin was only detected in one
of the samples in New vally, while aldrin was not detected in any of the samples.
However, from the 60 human milk samples, 5l% of the samples were free from any
detectable DDT levels. a fact which may suggest that there were no recent sources
of pollution by intact DDT (Saleh et al., 1996a,
Hexachlorocyclohexanes (HCH lsomers)
δ-HCH (lindane) was detected in 95% of the analyzes human milk samples.
The lowest levels were found in governorates between Cairo and Assiut and in
Suez (0.00-10.00 ppb), while the higher levels (10.00-33.00 ppb) were found
in the Delta area and in Alexandria. The higher levels could be a reflection
of the use of lindane in agriculture and in the control of cattle ecto-parasites.
Also, this might be due to the human consumption of large quantities of polluted
fatty fish. Several studies (Kucinski, 1986) have pointed
out the presence of organochlorine residues including lindane in different food
stuffs (meat, dairy products. grain and drinks).
|| Distribution of the main organochlorine insecticide residues
in Egyptian Mother's milk
|*No. of collection samples
These contaminated foods, which represent the basic staples for the donor
mothers, may explain the source of lindane in their milk. Another studies Saleh
et al. (1998, 1999) conducted on breast human
milk proved that samples containing relatively higher levels of DDT group (DDT,
DDE and DDD) showed significant effect on the level of lysozyme, lactalbumin
protein bands relative to low or no residue level.
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