The distribution, elimination, and in vivo biotransformation of aldicarb in the rainbow trout (Oncorhynchus mykiss)

FUNDAMENTAL

AND

APPLIED

TOXICOLOGY

18, 13 l- 136 (1992)

The Distribution, Elimination, and in Viva Biotransformation in the Rainbow Trout (Oncorhynchus mykiss)

of Aldicarb

DANIEL SCHLENK,**' DAVID A. ERICKSON,~,*JOHN J. LECH,~ AND DONALD R. BUHLER*.~ *Toxicology Program and Department of Agricultural Chemistry, Oregon State University, Corvallis, Oregon, and TDepartment of Pharmacology and Toxicology. Medical College of Wisconsin, Milwaukee, Wisconsin Received April 2, 1991; accepted July 19, 1991

mar and Pant, 1984; Pant et al., 1987), and the freshwater The Distribution, Elimination, and in Viva Biotransformation murrel (Channa guchua Hamilton) (Ali et al., 1985). As in of Aldicarb in the Rainbow Trout (Oncurhynchus mykiss). mammals, the toxicity of aldicarb in fish is brought about SCHLENK, D., ERICKSON, D. A., LECH, J. J., AND BUHLER, by its inactivation of acetylcholinesterase (Coppage, 1977); D. R. (1992). Fundurn. A&. Toxicol. 18, 131-136. however, little is known about the metabolic fate of aldicarb The distribution and elimination of (‘4C]aldicarb,administered in fish. orally and by intraperitoneal (ip) injection, wasexaminedin the The rainbow trout has been used extensively to study the rainbow trout (Oncorhynchusmykiss).Tissue residueswere de- toxicology of various chemicals in aquatic systems (Bailey termined by monitoring radioactivity at various time periodsup et al., 1984; McKim et al., 1987). The purpose of this paper to 96 hr in trout administered[14C]aldicarborally. Periodic water was to examine the tissue distribution, elimination, and biosamplesand a single tissueresidueradioactivity level were obtransformation of aldicarb in the rainbow trout in order to tained after 24 hr in free swimmingand spinally transectedfish which received [14C]aldicarbvia intraperitoneal injection. Aldi- gain a better understanding of the behavior of aldicarb in an carb appearsto be absorbedrapidly (99% within 3 hr) and dis- aquatic organism. tributed to all tissues.Elimination profiles from both dosage groupsdemonstratea rapid 01phase(oral 24 hr; ip 3 hr) probably MATERIALS AND METHODS due to branchial excretion (96% after ip injection) followed by Chemicals. Aldicarb, aldicarb sulfoxide, and aldicarb sulfone were oba slower p phase(oral 107 hr; ip 28 hr) suggestinga deeper compartment such as muscle.[‘4C]Aldicarb and/or its metabo- tained from the U.S. Environmental Protection Agency’s chemical repository lites were slowly being transported to the bile after 24 hr. The (Research Triangle Park, NC). [?Z]Aldicarb (9 mCi/mmol) and XAD4 in viva biotransformation of [14C]aldicarbwasexamined in spi- resin were purchased from Sigma Chemical Co. (St. Louis, MO). Aldicarb nally transectedtrout 24 hr after ip injection. The major me- oxime and nitrile were synthesized via base-catalyzed hydrolysis of aldicarb (Payne et al., 1966). Likewise, aldicarb sulfoxide oxime and aldicarb sulfoxide tabolite found was aldicarb sulfoxide (7.6%) along with lesser nitrile were products of base-catalyzed hydrolysis of aldicarb sulfoxide. amountsof aldicarb oxime (5.4%). 8 1992 Society of Toxicology.

Animals-Oral sfudies. Rainbow trout weighing from 170 to 530 g were held at 12°C in dechlorinated Milwaukee city water during the study at the Medical College of Wisconsin. All animals were acclimated to laboratory Aldicarb (Temik) is a carbamate pesticide which is used conditions for at least 6 months prior to use. The trout were fasted for 3 throughout the world to control insects and nematodes days prior to receiving a gavage treatment. Trout were dosed with a food (Risher et al., 1987). The toxicity of aldicarb is mediated slurry prepared from Nelson’s Siver Cup trout pellets (Murray, UT). [%]AIdicarb was thoroughly mixed into the food sluny immediately prior through inactivation of the enzyme, acetylcholinesterase to treatment. While the target concentration of [‘4C]aldicarb was 25 /Ig/ml. (Knaak et al., 1966). Since aldicarb and its metabolites are the concentration of the pesticide actually in the diet was later found to be relatively water soluble, aquatic organisms have a great po- 24 pg/ml when checked by scintillation counting. Fish were dosed with 48 pg aldicarb/kg body wt (2 ml food slurry/kg body wt). The trout were cooled tential for exposure to thesechemicalsvia agricultural runoff. The acute toxicity of aldicarb hasbeen examined in several in ice water immediately prior to gavagetreatment and placed into a holding tank containing water at 12°C immediately after gavage treatment. While fish species:the common snook (Centropomus undecimalis) in the holding tank, the fish were observed in order to ensure that the adand sheepsheadminnow (Cyprinodon variegatus) (Landau ministered dose was not regurgitated. Animals that did not regurgitate were and Tucker, 1984), the Rosy barb (Barbus conchonius) (Ku- placed into the experimental tanks. Tissue sampling. At 3, 6, 12, 24, 48, and 96 hr after gavage treatment, ’ Present address: Division of Toxicology, University of Arkansas for four trout were sampled from the experimental tanks. Euthanasia was performed by delivering a sharp blow to the head of the fish. The various body Medical Sciences, Little Rock, AR 72205. 2 Present address:c/o Boehringer Ingelheim Pharmaceuticals. 900 E. Ridge, tissues of the trout were dissected and weighed. The tissues were then subP.O. Box 368, Ridgefield, CT 06877. sampled and placed into the tissue solubilizer. When the subsamples were 3 To whom correspondence should be addressed. dissolved. the radioactivity was quantified by scintillation counting. 131

0272-0590/92 $3.00 Copyright All rights

0

1992 by the Society

of Toxicology.

of reproduction in any form reserved.

132

SCHLENK

ET AL.

TABLE 1 Relative [14C]AldicarbResidues(rig/g Tissue)Remaining in the Body Tissuesof Rainbow Trout over Time Following Gavage Treatment (48 pg/kg body wt) Time (hr) Tissue Gills Heart Ant. Intestine Post. Intestine Ant. Kidney Post Kidney Liver Muscle Pyloric Caeca Intest. Contents Spleen Stomach Fat Whole Blood Bile

6

3 71.0 46.6 62.2 33.0 42.7 37.9 113.0 21.8 69.9 91.0 48.7 515.8 16.6 28.8 40.7

f 37.9 f 3.5 12.4 5.4 5.9 2.8 28.5 -c 4.1 + 11.8 f 17.2 k 9.6 + 122.4 f 3.0 2 4.3 k 12.4 f f i k k

48.9 47.0 41.3 35.4 28.1 31.8 61.4 20.7 67.9 134.2 30.4 157.5 12.5 28.5 49.1

2 12.6 + 10.6 9.0 9.2 2.4 5.0 7.0 3.9 24.1 _+ 77.5 f 4.0 + 29.8 f 5.1 k 3.4 k 6.0 * t k k + k +

12

24

48

19.1 2 1.1 47.7 + 4.5 53.6 f 6.9 27.0 f 3.1 23.4 i 1.5 22.6 + 2.7 38.7 f 6.4 20.6 f 1.6 56.9 f 9.5 176.2 + 48.4 22.4 f 1.9 91.1 -+ 13.8 4.6 _+ 1.0 20.7 f 1.6 216.1 + 20.5

13.0 -t 0.6 34.5 -+ 2.0 38.1 k 6.4 22.4 t 2.2 17.7 t 1.8 19.5 + 1.5 31.8 i 3.1 13.9 A 1.0 46.9 f 7.5 218.6 + 36.3 19.6 r 0.5 51.5 -t 7.5 2.0 f 0.6 11.9 It 0.4 257 -t 55.0

11.1 2 1.0 26.2 + 1.8 27.0 + 2.0 20.7 + 2.1 11.02 2.6 13.1 2 1.7 28.4 _+ 4.8 11.4 + 1.1 28.5 + 3.1 195.7 + 28.5 13.6 rt 2.4 37.5 f 11.5 1.2 * 0.3 10.7 f 1.8 291.8 + 59.1

Animals-Intraperitoneal studies. Rainbow trout (130-200 g) were isolated individually in separate aquaria (12°C) at the Oregon State University Marine Freshwater Biomedical Center, not fed for 24 hr, and immobilized by spinal transection utilizing MS-222 as anesthetic (McKim et nl., 1987). Postoperative fish were housed in a rectangular Plexiglass metabolism chamber 18 X 6 X 4 in. The approximate water depth was 5 in. After spinal transection and catheterization for urine collection, fish were allowed to equilibrate braced in an upright position within the chamber for 2-3 days before chemical administration. By placing valves in the anterior and posterior sections of the chamber, well water could flow through the chamber at approximately 500 ml/min allowing equilibration. However, upon injection of the fish with [i4C]a1dicarb, the valveswere closed and air stones were added to create a static system. Tissue sampling. Three transected fish and three nontransected fish were injected ip with 1 mg/kg [‘4C]aldicarb (2.3 &i/pmol). In order to prevent toxicity, the arbitrary dose given to trout was approximately eight times less than the 96-hr LC50 value of 8 mg/liter obtained from the Hazardous Substances Data Base. The fish did not display convulsions or other overt signs of toxicity. However, there appeared to be a consistent occurrence of mucus release from the gills. Fish were maintained in aerated static chambers during the experiments. The total volume of water was siphoned out of the chambers at various time points (0.5, 1.O,2.0,4.0,8.0, 13.0, and 24.0 hr postinjection), the radioactivity in an aliquot was measured, and then fresh water was returned to the chamber. After 24 hr, the fish were euthanized by striking them on the head and the bile was sampled for metabolism studies. Kinetic elimination phases were calculated by curve stripping using a two-compartment body model. Tissue subsamples were then treated with solubilizer and hydrogen peroxide and radioactivity was measured via scintillation counting. Excretory roate studies. Following a 2-3 day equilibration period, two transected trout with urinary catheters were injected ip with 1.0 mg/kg [?]aldicarb (0.5 &i/rmol). Epidermal mucus was scraped from the dorsal portion of the lateral line at 1.O,2.0,4.0,8.0, 13.0, and 24.0 hr postinjection, placed in preweighed glass scintillation vials, and subsequently counted. An aliquot of collected urine and bile samples was taken 24 hr postinjection and counted via scintillation. Metabolism studies. A recirculating chemical extraction systemwas devised to remove excreted radioactivity from the water for metabolite iden-

96 10.2 f 18.0 f 17.8 f 17.0 f 11.9* 10.9 * 18.2 f 8.0 + 19.0 f 198.8 _i 16.0 + 25.9 f 2.5 + 5.8 f 460.5 f

1.4 2.1 2.6 2.3 1.3 1.5 1.9 1.2 2.4 35.4 1.3 4.9 0.5 1.0 92.2

tification. Water was pumped at approximately 15-20 ml/min via PVC tubing through a glass column containing 20 ml of methanol-extracted XAD4 resin (Junk et al.. 1974). Trapping efficiency of the resin was determined by periodically collecting water samples from the chamber after administration of a known quantity of radiolabel and counted via scintillation. Prior to the addition of fish. the metabolic chamber was filled with water and [“‘C]aldicarb was added to determine the extraction efficiency of the XAD4 resin and to examine the possibility of nonenzymatic metabolite formation. Extraction efficiency was 100% and no metabolites were observed upon HPLC analysis. The chamber was partially submerged by free-flowing well water to maintain a constant temperature of 12°C. After 24 hr, the resin was then sequentially extracted with 50 ml of methanol, 50 ml of dichloromethane:methanol (1: I), 50 ml of dichloromethane, and a final 100-m] wash with methanol. Each of these fractions was evaporated to dryness and taken up in 0.25 ml of methanol. A 50+1 aliquot of each fraction was then injected onto a Whatman C-8 column utilizing a Spectra Physics 8000 highperformance liquid chromatography (HPLC) system. The solvent system, a modification of Miles and Delfino ( 1984), was 12% acetonitrile and water for 10 min and a 2-minute gradient increase to 40% acetonitrile for 8 min. Column effluent was collected at 1.O-min intervals in scintillation vials and counted on a Packard scintillation counter. Radioactive metabolites were also quantitated utilizing a Beckman 171 radioisotope detector on a Shimadzu LC-6A HPLC system. Recovered radioactivity was compared with the retention time of known standards. Metabolites were also separated and identified utilizing thin-layer chromatography (TLC) employing an acetone:benzene (3: 1) solvent systemand iodine crystals for visual detection. Urine and bile were filtered through a 0.5~pm Millipore filter and a 50-~1 aliquot was directly analyzed via HPLC.

RESULTS

Oral Administration The oral dose of aldicarb was absorbed rapidly with 1.13% of the total dose remaining in the intestinal contents after 3 hr (Table 1). However, only 45% of the total dose was present in the animal at this time indicating a rapid elimination of

ALDICARB

DISPOSITION

133

IN TROUT

t 112 (alpha) q 24 hr. t 112 (beta) = 107 hr.

Q3GLWSTI

HTKSPBMEC

Tissue a

10

I 24

0

”

’

I ’ 48 TIME (hours)

*

’

I 72

s

”

I 96

FIG. 3. The tissue distribution of [14C]aldicarb in transected and freeswimming ip injected rainbow trout. Each value represents the mean of three individual fish + SD. (GB, bile; G, gill; L, liver; HK, anterior kidney; ST, stomach; I, intestine; H, heart: TK, posterior kidney; SP, spleen; B, brain; M, muscle; E, eye; C, pyloric caeca).

FIG. 1. The whole body elimination profile of [r4C]aldicarb in orally dosed rainbow trout. Each value represents the mean of four individual fish + SD.

Intraperitoneal

the absorbed material. The whole body depuration appears to be biphasic (Fig. 1) with LYand ,6 phase half-lives of approximately 24 and 107 hr, respectively. Aldicarb and/or its metabolites accumulated rapidly in all tissues especially in the stomach, liver, gills, pyloric caeca, heart, bile, and intestine (Table 1). After 96 hr, 14% of the administered dose was still present in the animal with radioactivity in muscle accounting for approximately half of the remaining residue (7.8 1 4 1.26%). Most tissue levels decreased over time; however, the concentration of radioactivity in the bile and intestinal contents slowly rose indicating the biliary excretion of aldicarb and/or its metabolites after dosing the trout orally.

Whole-body elimination of radioactivity was similar for transected and nontransected rainbow trout (Fig. 2). The mean CIconstants (N = 3) for nontransected (2.32 hr’) and transected (3.24 hr’) fish and /3 constants for nontransected (28.4 hr’) and transected (25.3 hr’) fish were not statistically different. After 24 hr, 84.6 k 6% of the injected dose was eliminated by both groups of fish. Consequently, subsequent metabolite collection procedures were performed for a 24hr period. There were no significant differences in tissue distribution of radioactivity in transected and nontransected animals (Fig. 3). Tissues possessing the highest relative levels of radioactivity (nmol/g) were stomach, caeca, liver, heart, and bile. Residual levels in muscle accounted for 54.0 k 11.2% of the remaining radioactivity. Total percentage recovery of injected radioactivity (tissue levels + urine metabolites + XAD resin metabolites) was 94.7 + 5%.

Administration

“V - -

”

Non-trans.

p t l/2

= 28.4

hr

Transected

p t l/2

= 25.3

hr

I

0

-8

lb

2’0

Time

30

Bile

0.2

(hr) a

FIG. 2. The whole body elimination profiles of [“‘Claldicarb in transected and freeswimming ip injected trout as estimated by the difference between the administered dose minus the excreted radioactivity. Each value represents the mean of three individual fish rt- SD.

I 20

-

I. 40

Percent

I. 65

I 80

.I

100

Excretion

FIG. 4. [‘4C]Aldicarb excretion profile in ip injected rainbow trout. Each value represents the average of two individual fish.

134

SCHLENK

Excretion of radioactivity appeared to be primarily via the gills (96.2%) (Fig. 4). Branchial elimination was determined indirectly by process of elimination. There was no radioactivity detected above background from dermal scraping and very little radioactivity present in the bile sampled 24 hr after injection (0.2%). Since a urinary catheter was responsible for collecting urinary radioactivity (3.6%) the remaining excretion alternatives were intestinal and branchial elimination pathways. However, since no fecal material was observed and rapid elimination was demonstrated in the previous pharmacokinetic studies, branchial elimination was the most probable route. The mean urinary flow rate (N = 2) was 12.2 ml collected per 24 hr. Aldicarb and its metabolites were separated utilizing an acetonitrile:water solvent system (Fig. 5). The retention times for the metabolites were as follows: aldicarb sulfoxide oxime (4 min); aldicarb sulfoxide nitrile (6 min); aldicarb sulfoxide (8 min); aldicarb sulfone (13.5 min); aldicarb nitrile (20 min); aldicarb oxime (22 min); aldicarb (25 min). Aldicarb, aldicarb nitrile, and aldicarb oxime possessed slightly lower retention times as measured on the Shimadzu LCdA HPLC system utilizing the Beckman 17 1 radioisotope detector. The average percentage conversion (N = 2) of [ 14C]aldicarb to metabolites by trout was 14.3%. The predominant metabolite observed in urine and water was aldicarb sulfoxide (Fig. 6). The sulfoxide accounted for an average of 7.6% of the total dose of [14C]aldicarb (N = 2). Other metabolites present in vivo were aldicarb sulfoxide oxime (0.88%) and the hydrolytic products aldicarb oxime (5.4%) and aldicarb nitrile (0.56%). DISCUSSION Aldicarb is a frequent contaminant of the aquatic environment because of its widespread use as a pesticide to con-

Aldicar Sulfoxidr

oxime Oxime

Sulfaxide

nitrile Nitrile

I

I 1’0

I 15 Time (mid

I 20

I 25

FIG. 5. HPLC trace demonstrating the separation of aldicarb and metabolites.

ET AL. 0.3

Sulfox

oxime

Sulfoxlde

oxime

nitrile

FIG. 6. In vivo metabolite profile of [%]aldicarb in ip injected rainbow trout. Each value represents the average of two individual fish.

trol insects and nematodes and its high water solubility (Brigs and Lord, 1983; Risher et al., 1987). While there have been some studies on the toxicity of aldicarb to fish (Ali et al., 1985; Kumar and Pant, 1984; Landau and Tucker, 1984; Pant et al., 1987), no reports have appeared on the pharmacokinetics and biotransformation of the pesticide in aquatic species. Aldicarb appears to be rapidly absorbed and distributed to all tissues in trout given [‘4C]aldicarb orally (Table 1). Approximately 98% of the radioactivity was no longer present in the intestinal contents 3 hr after gavage treatment. Each of the 13 tissues dissected from po-exposed trout possessed varied levels of radioactivity indicating a diffuse distribution of radiolabel after 3 hr. Initially, levels of radioactivity were higher in the muscle, stomach, gills, blood, liver, and pyloric caeca. After 96 hr, with the exception of muscle, most of the radioactivity in these tissues was eliminated or transferred to other compartments, such as the bile. In rats given aldicarb by oral administration, absorption was likewise rapid and residues were found in all 13 tissues examined with each tissue containing similar levels 24 hr after treatment (Andrawes et al., 1967). In trout injected with [14C]aldicarb, dispositional data paralleled that observed in gavage-treated trout. After 24 hr, all of the 13 tissues examined had radioactivity residues of differing content. The stomach, pyloric caeca, liver, and heart possessed the highest relative levels after 24 hr which was also observed in the 24-hr time point with trout given aldicarb orally. After an initially rapid elimination phase, approximately 15% of the injected dose remained in the fish after 24 hr, predominantly concentrated in the muscle (54.0%). Likewise, in orally dosed trout, approximately 20% of the administered dose was still present in the fish after 24 hr and muscle residues also accounted for more than half of the radioactivity. In trout administered aldicarb by gavage and injection, a rapid elimination phase was followed by a slower release of radiolabel indicating a two-compartment model. The major

ALDICARB

DISPOSITION

route of elimination of aldicarb in trout injected with radiolabel was via the gill which was consistent with the rapid (Y phase constants observed in transected and free-swimming animals. The gill appears to be an important organ for xenobiotic elimination in fish possibly due to its high surface area and large cardiac output. Dauble et al. (1987) have shown that quinoline elimination in the rainbow trout was rapid and primarily via the branchial route. Since aldicarb possessesa log P value of 1.13, it would be expected to readily cross the gill membrane and be eliminated. McKim et al. (1987) have shown that chemicals having log P values less than 3 rapidly crossed the gill membrane in rainbow trout. In mammals, the main route of aldicarb elimination is via the urine (Andrawes et al., 1967). This route of excretion in trout, however, is minor with only aldicarb sulfoxide and aldicarb sulfoxide oxime being detected in trout urine. The parent pesticide was not observed. It is possible that the remaining aldicarb which is not excreted via the gill may be oxygenated in the kidney to the sulfoxide and eliminated through the urine. There may also be active transport processes that may excrete sulfoxide but not parent. Although very little radioactivity was present from fresh bile samples taken from fish 24 hr postinjection, it is important to note that the samples obtained were just above the limits of detection due to the quenching effect of bile in the scintillation process. Thus, the pesticide and its metabolites in these samples may have been underestimated. Furthermore, the occurrence of increasing levels of radioactivity in bile after 24 hr in orally dosed trout indicates biliary elimination as a possible route after initial branchial elimination. Since muscle accounts for the majority of the fish weight, it is not surprising that a chemical which is rapidly distributed occurs in such great amounts in that tissue. However, it is intriguing that muscle appears to take up radiolabel rapidly, but seems to eliminate the chemical slowly. The slow elimination of radioactivity from muscle indicates that muscle may exist as the deep compartment responsible for the longer /3 elimination phase. Aldicarb toxicity in fish is mediated by its inhibition of acetylcholinesterase leading to enhanced levels of the neurotransmitter, acetylcholine, subsequent cholinergic overload and, depending on the dose, death of the organism (Coppage, 1977). S-oxidation of aldicarb to the sulfoxide has been shown to potentiate inhibition of acetylcholinesterase 76fold (NIH, 1979). Consequently, s-oxidation of aldicarb can be considered a pathway of bioactivation producing a more toxic chemical. To confirm this fact, four rainbow trout (250 g) were administered aldicarb sulfoxide intraperitoneally at the same dose that [14C]aldicarb was given in our metabolism studies (1 mg/kg). Within 10 min, all of the fish died, exhibiting severe convulsions prior to death (data not shown). Since hydrolysis of aldicarb to aldicarb nitrile or aldicarb oxime essentially eliminates its properties of acetylcholin-

135

IN TROUT

esterase inhibition, this metabolic pathway can be considered a route of detoxification. The proposed metabolic pathway for aldicarb in the rainbow trout can be observed in Fig. 7. Since there were no significant dispositional differences between transected and free-swimming trout, transected animals could be used to examine the in vivo biotransformation of aldicarb. Aldicarb sulfoxide constituted 7.6% of the injected dose of [i4C]aldicarb with lesser amounts of aldicarb oxime, aldicarb sulfoxide oxime, and aldicarb nitrile. The in vivo formation of the two oximes and aldicarb nitrile was probably a result of the hydrolytic action of plasma esterases since there were minimal amounts of hydrolytic metabolites observed in vitro. The low levels of hydrolysis observed with aldicarb biotransformation in this study were very similar to the low plasma esterase activity observed in rainbow trout by Glickman and Lech (1981). Even though aldicarb sulfoxide was the major metabolite observed, the levels of sulfoxide detected were probably underestimated due to the occurrence of thioreductases throughout the organism which could catalyze reduction of the sulfoxide back to the sulfide (Mannervik, 1982; Tatsumi, 1982; Ziegler, 1988). However, the formation of aldicarb sulfoxide in vivo is consistent with previous work which examined the in vitro biotransformation profile of aldicarb in microsomes from trout liver, kidney, and gill (Schlenk and Buhler, 199 1). Similar dispositional results obtained in two separate laboratories using rainbow trout indicate that aldicarb was rapidly absorbed and that the elimination profiles from oral and intraperitoneal administration fit a two-compartment model. Aldicarb was initially eliminated from the gill and then slowly released from the bile. The major metabolite after 24 hr was aldicarb sulfoxide indicating the potential of the trout to bioactivate aldicarb to a more toxic species. Since the rainbow trout is gaining widespread use as an alternative vertebrate model to perform toxicological evaluations at reduced costs, the disposition of more xenobiotics should be examined in this species. fH3

f

CH,S-CCH=NOCNHCH3

y3

b

7’43

CH,S-yCH=NOH -

hH,

CH3S-7eN

CH3

aldicarb

aldicarb

CH3

oxime

aldicarb

nitrile

1 ?7’-‘3

o ?

CH3S-yCH=NOtNHCH, CH3 aldicarb

-

FH3

CH,S-CCH=NOH AH3

sulfoxide

sulfoxide

oxime

FIG. ‘7. Proposed metabolic pathway of [‘4C]aldicarb in ip injected rainbow trout.

136

SCHLENK

ACKNOWLEDGMENTS We thank Mr. Theodore Will for his assistance in fish maintenance and euthanization. We also thank Dr. James McKim, Dr. Dennis Dauble, and Ms. Patricia Schmieder for their help in setting up the in viva metabolic chamber experiments. This research was supported by grants from the National Institute of Environmental Health Sciences (ES002 10, ES03850, ES07060, and ES01080 (J.J.L.)). This paper was issued as Technical Paper No. 9406 from the Oregon Agricultural Experiment Station.

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12, 107- 111.

Andrawes, N. R., Dorough, H. W., and Lindquist, D. A. (1967). Degradation and elimination of temik in rats. J. Econ. Entomol. 60, 979-987. Bailey, G. S., Hendricks, J. D., Nixon, J. E., and Pawlowski, N. E. (1984). The sensitivity of rainbow trout and other fish to carcinogens. Drug Metab. Rev. 15, 725-750.

Briggs, G. G., and Lord, K. A. (1983). The distribution of aldicarb and its metabolites between Lumbricus terrestris, water and soil. Pestic. Sci. 14, 412-416. Coppage, D. L. (1977). Anticholinesterase action of pesticidal carbamates in the central nervous systemof poisoned fishes.In PhysiologicaL Responses ofMarine Biota to Pollutants(J. F. Vemberg. Ed.), pp. 93-102. Academic Press, New York. Dauble, D. D., Bean, R. M., and Carlile, D. W. (1987). Uptake, distribution, and elimination of dietary quinoline by rainbow trout (Sulmo guirdneri). Camp.

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Glickman, A. H., and Lech, J. J. (1981). Hydrolysis of permethrin, a pyrethroid insecticide, by rainbow trout and mouse tissues in vitro: A comparative study. Toxicol. Appl. Pharmacol. 60, 186- 192. Junk, G. A., Richard, J. J., Grieser, M. D., Witiak, D., Witiak, J. L., Arguello, M. D., Vick, R., Svec, H. J., Fritz, J. S., and Calder, G. V. (1974). Use of macroreticular resins in the analysis of water for trace organic contaminants. J. Chromatogr. 99, 745-762. Knaak, J. B., Tallant, M. J., and Sullivan, L. J. (1966). The metabolism of 2-methyl-2-(methylthio)proprionaldehyde O-(methylcarbamoyl) oxime in the rat. J. Agr. Food Chem. 14,573-578.

ET AL. Kumar, S., and Pant, S. C. (1984). Qrganal damage caused by aldicarb to a freshwater teleost Barbus conchonius Hamilton. Bull. Environ. Contam. Toxicol.

33, 50-5.5.

Landau, M., and Tucker, J. W., Jr. (1984). Acute toxicity of ethylene dibromide and aldicarb to young of 2 estuarine fish species. Bull. Environ. Contam. Toxicol. 33, 127-132. Mannervik, B. (1982). Mercaptans. In Metabolic Basis of Detoxication (W. B. Jakoby, J. R. Bend, and J. Caldwell, Eds.), pp. 185-206. Academic Press, New York. McKim, J. M., Bradbury, S. P., and Niemi, G. J. (1987). Fish acute toxicity syndromes and their use in the QSAR approach to hazard assessment. Environ. Health Perspect. 71, 171-186. Miles, C. J.. and Delfino, J. J. (1984). Determination of aldicarb and its derivatives in groundwater by high-performance liquid chromatography with UV detection. J. Chromatogr. 299, 275-280. National Institutes of Health ( 1979). Toxicology of Aldicarb. Publication No. 79- 139 1.

and Carcinogenesis

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Pant, J., Tewari, H., and Gill, T. S. (1987). Effects of aldicarb on the blood and tissues of a freshwater fish. Bull. Environ. Contam. Toxicol. 38, 3641. Payne, L. K., Jr., Stansbury, H. A., Jr., and Weiden, M. H. J. (1966). The synthesis and insecticidal properties of some choline&c trisubstituted acetaldehyde O-(methylcarbamoyl)oximes. J. Agr. Food Chem. 14, 356365. Risher, J. F., Mink, F. L., and Stara, J. F. (1987). The toxicologic effects of the carbamate insecticide aldicarb in mammals: A review. Environ. Health Perspect.

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Schlenk, D., and Buhler, D. R. (199 1). Role of flavin-containing monooxygenase in the in vitro biotransformation of aldicarb in the rainbow trout (Oncorhynchus mykiss). Xenobiotica. in press. Tatsumi, K. (1982). Sulfoxide-reducing enzyme systemsresponsible for activation and inactivation of sulfoxide compounds. In Microsomes, Drug Oxidations and Drug Toxicity (R. Sato, and R. Kato, Eds.), pp. 471-477. Wiley, New York. Ziegler, D. M. (1988). Flavin-containing monooxygenases: Catalytic mechanism and substrate specificities. Drug Metab. Rev. 19, l-23.