Dermal Dose-Cholinesterase Response and Percutaneous

5 Dermal Dose-Cholinesterase Response and Percutaneous Absorption Studies with Several Cholinesterase Inhibitors 1

2

JAMES B. KNAAK and BARRY W. WILSON

Downloaded by COLUMBIA UNIV on March 9, 2013 | http://pubs.acs.org Publication Date: February 25, 1985 | doi: 10.1021/bk-1985-0273.ch005

1

Worker Health and Safety Unit, California Department of Food and Agriculture, Sacramento, CA 95814 Department of Avian Sciences, University of California, Davis, CA 95616

2

Dermal dose-ChE response and percutaneous absorption studies were conducted with parathion, carbaryl, and thiodicarb in the rat. Parathion and thiodicarb inhibited 50% of the red cell cholinesterase activity at dose levels of 3.2 and 33 mg/kg of bw. Carbaryl at the highest dose level tested (417 mg/kg of bw) produced no detectable red cell cholinesterase inhibition. Finite, nonoccluded doses (600 ug) of [ C]labeled parathion and carbaryl were absorbed through the back skin of adult males at the rate of 0.33 and 0.18 ug hr cm of skin. This rate was sufficient to absorb 57% of the applied dose of parathion and carbaryl over a period of 168 hr. A computer program, Nonlin, was used to calculate the plasma rate constants for simultaneous absorption-elimination. A finite, nonoccluded dose (570 ug) of [ C] thiodicarb was slowly absorbed (0.042 to 0.27 ug hr cm of skin) and acted as if it were an infinite dose applied to the skin. Approximately 22% of the applied dose was absorbed over a period of 168 hr. 14

-1

-2

14

-1

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C h o l i n e s t e r a s e (ChE) i n h i b i t i n g organophosphate and carbamate insecticides are used extensively in C a l i f o r n i a a g r i c u l t u r e . Workers are exposed to these insecticides during mixing/loading and a p p l i cation and by contacting f o l i a r residues during harvest operations (1.2.3). Exposure to spray and f o l i a r residues often results in the i n h i b i t i o n of red blood c e l l cholinesterase a c t i v i t y and reported i l l n e s s e s among farm workers ( A ) · The r e l a t i o n s h i p , in workers, between exposure to pesticides, the rate they are absorbed, and cholinesterase i n h i b i t i o n is not well known. F i e l d monitoring studies indicate that prolonged exposure to moderately toxic organophosphates (OP's) produce the same amount of ChE i n h i b i t i o n ( £ ) as short exposures to highly toxic OP's (3). The C a l i f o r n i a Department of Food and A g r i c u l t u r e r e c e n t l y established t o x i c o l o g i c a l l y safe levels for t o t a l residues of parathion [0,0-diethyl 0-(4-nitropheny1) phosphorothioate] , 0097-6156/85/0273-0063$06.00/0 © 1985 A m e r i c a n C h e m i c a l Society

In Dermal Exposure Related to Pesticide Use; Honeycutt, R., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1985.

DERMAL EXPOSURE RELATED TO PESTICIDE USE


64

azinphosmethyl [Ο,Ο-dimethyl S-[(4-oxo-l,2,3-benzotriazin-3(4H)-yl) methyl] phosphorodithioate], and methidathion [S-[(5-methoxy-2-oxo1,3,4-thiadiazol-3 (2H)-yl)methyl] Ο,Ο-dimethyl phosphorodithioate] and their toxic a l t e r a t i o n products on tree foliage (£) using dermal dose-ChE response data. This procedure was also used to establish reentry times for chlorthiophos [0-[2,5-dichloro-4-(methylthio)phenyl] 0,0-diethyl phosphorothioate] and carbosulfan [dihydro-2,2dimethyl-7-benzo-furanyl [(di-n-butylamino)thio] methylcarbamate] (LJ). The differences observed between chlorthiophos, carbosulfan, and other pesticides that have been examined appear to be largely due to t h e i r r a t e of a b s o r p t i o n , and anti-ChE a c t i v i t y . These r e l a t i o n s h i p s were r e c e n t l y examined f o r c a r b a r y l [1-naphthyl methylcarbamate] , p a r a t h i o n (9) and t h i o d i c a r b [dimethyl Ν,N* [thiobis[(methylimido)carbonyloxy]] bis [ethanimidothioate]] (10) in the Sprague-Dawley rat and are reviewed i n this paper. Methods Dermal Dose-ChE Response Studies. A procedure developed by Knaak et a l . (11) using 220-240 g male Sprague-Dawley rats was used to determine the relationship between the applied dose and red c e l l ChE i n h i b i t i o n . Four rats per dose level and four or five dosage levels were used. In each study, baseline or control ChE a c t i v i t y was determined using nontreated animals. The pesticides (carbaryl, parathion and t h i o d i c a r b ) were i n d i v i d u a l l y applied in 1.0 ml of acetone to the clipped backs, 25 cm , of the rat using a d i g i t a l m i c r o l i t e r pipet. Animals treated with parathion were k i l l e d 72 hr after the application of the dose, while animals treated with carbam ates; carbaryl, and thiodicarb were k i l l e d 24 hr after the dose was applied. The log-probit procedure of Finney (12.) for determining LD values was modified to compute the i n h i b i t i o n ED for c h o l i nesterase a c t i v i t y (11) using treatment and control means. The program computed the slope of the l i n e , the ED and the confidence l i m i t s for the curves. n

n

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Percutaneous Absorption Studies. The percutaneous absorption of [rjng-U-14 C] parathion ( s p e c i f i c a c t i v i t y , 1.8 mCi/mmole), [ringU-j^c]carbaryl ( s p e c i f i c a c t i v i t y , 1.46 mCi/mmole) (j)) and [acetyl1C] t h i o d i c a r b ( s p e c i f i c a c t i v i t y 2.19 mCi/mmole) (IQ) were studied using the procedures of Knaak et a l . (13) for triadimefon. Adult male and female Sprague-Dawley rats were used i n the studies with parathion, adult males with carbaryl, and adult females with thiodicarb. Rats were prepared for dosing, one day prior to t r e a t ment, by removing the hair on their backs with an animal clipper. Templates, cut from neoprene rubber sheeting, were glued to the backs of the animals using a cyanoacrylate glue. The treatment areas (A • 9.64 weight 0·66), comprising 3% of the body surface, were determined using the body weight to surface area data of Brodie et a l . (14). Queen Anne c o l l a r s made of polyethylene sheeting were used to prevent the animals from reaching the treated areas. In each study, 36 rats (12 groups of 3 rats per group) were used. The dose (600 ug of parathion or carbaryl; 570 ug of thiodicarb), ^in 0.2 ml of acetone, was evenly distributed over a 11.9 to 13.8 cm area using a d i g i t a l m i c r o l i t e r p i p e t to give approximately 43.5 to 48 ug/cm . The 2


5. K N A A K A N D WILSON

Dermal

Dose-Cholinesterase

Response

65


animals were placed into individual metabolism cages for the complete and separate c o l l e c t i o n of urine and feces. Three animals were k i l l e d at 0.5, 1, 4, 8, 12, 24, 48, 72, 96, 120, 144, and 168 hr after the administration of the dose. Plasma, treated skin, acetone washings from treated skin, heart, l i v e r , kidney, and the carcass from each animal were c o l l e c t e d at s a c r i f i c e . Urine and f e c a l samples were collected every 24 hr during the study. Penetrated skin residues were extracted using methanol followed by acetone. Unextracted residues were considered to be bound to tissue. Liquid samples were analyzed by direct s c i n t i l l a t i o n counting methods and t i s s u e / f e c a l samples by combusting procedures (13). Calculations. The count data from the percutaneous a b s o r p t i o n studies were analyzed by the procedures o f Knaak et a l . , (T3) u t i l i zing a c o l l e c t i o n of computer programs: a conversion program, dpm to ug of pesticide or pesticide equivalents; exponential and l i n e a r regression programs of Heilborn (.15). The blood plasma data was analyzed using the two compartment model o f Metzler et a l . (16), where k.^ and k«Q are the f i r s t order rate constants f o r absorption into and elimination from plasma. The entry compartment, A, i s represented by skin while the main compartment, B, i s represented by plasma as shown in Figure 1. The dose, t o p i c a l l y applied, i s absorbed (penetrates) by the skin (entry compartment). The rate of absorption (penetration) was obtained i n d i r e c t l y by measuring the r a t e the dose i s l o s t from s k i n ( s u r f a c e , penetrated and bound residues) or eliminated from plasma (13)· T h skin absorption rates were calculated using a modification of the procedure of M a r z u l l i et a l . (17). e

Results Dermal Dose-Response Studies. The dermal dose red c e l l ChE-response curves f o r parathion and thiodicarb are given i n Figure 2. Parathion, the most toxic pesticide used, inhibited 50% of the red c e l l ChE a c t i v i t y at a dose level jpf 31 ug/cm (3.2 mg/kg) o f treated skin i n 72 hr, while 322 ug/cm of thiodicarb (33.3 mg/kg) gave 50^ ChE i n h i b i t i o n i n 24 hr. Carbaryl at dose levels up to 4,000 ug/cm of treated skin (417 mg/kg) did not produce detectable ChE i n h i b i t i o n 24 hr after application of the dose. Thiodicarb was dermally more toxic than carbaryl, but substantially less toxic (1/10) than parathion. 2 A dose of 800 ug o f thiodicarb per cm o f 2 s k i n produced the same amount of i n h i b i t i o n as a dose o f 400 ug/cm . Doses o f parathion above 80 ug/cm inhibited 70 to 100 % of red c e l l cholinesterase a c t i v i t y and produced mortality i n test animals. No deaths occurred using doses of 800 ug o f thiodicarb per cm of skin. 14 Recovery S t u d i e s . The time-course r e c o v e r i e s of [ C ] l a b e l e d parathion, carbaryl, and thiodicarb i n adult rats are given i n Figure 3. The recovery data i n this Figure are given i n percentage of the applied dose, except f o r urine and feces which are expressed i n cumulative percentage of dose. Total recovery i s a summation o f the percentages obtained for feces, urine, carcass, and skin. Parathion was excreted i n urine (47, 49%) and i n feces (5.3, 3.7%) by males and females. Recovery procedures accounted for 61% of the dose for adult In Dermal Exposure Related to Pesticide Use; Honeycutt, R., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1985.


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5.

KNAAK AND WILSON

Dermal

Dose-Cholinesterase

Response

F i g u r e 3. Time-course r e c o v e r y o f d e r m a l l y a p p l i e d [ C] l a b e l e d p a r a t h i o n , c a r b a r y l , and t h i o d i c a r b e q u i v a l e n t s i n p e r c e n t a g e o f dose i n f e c e s , u r i n e , c a r c a s s e s , and s k i n ( s u r f a c e and p e n e t r a t e d r e s i d u e s ) a f t e r a p p l i c a t i o n . (Reproduced w i t h p e r m i s s i o n from Ref. 9. C o p y r i g h t 1984, Academic P r e s s . )


67

68



males and females at the end o f the study. Carbaryl equivalents were largely excreted i n urine (39%) with lesser amounts i n feces (15%). Thiodicarb was not absorbed to any extent. Approximately 4.4% was found i n u r i n e , 2.5% i n f e c e s , 8.8% i n the c a r c a s s , and 6.6% (estimated) i n r e s p i r a t o r y a i r as CO^ and a c e t o n i t r i l e . The largest percentage o f the dose was found on the surface o f the skin. Evaporative losses are believed to be responsible for the incomplete recovery of the applied dose i n these studies. 14 Loss From Skin. The d i s s i p a t i o n of t o p i c a l l y applied [ C]parathion and [ 1*+C]carbaryl from skin^ is given i n Figure 4, while Figure 5 gives the d i s s i p a t i o n o f [ C] thiodicarb. The h a l f - l i v e s f o r the d i s s i p a t i o n of parathion from the skin of adult females and males were 24.3 and 28.6 hr, respectively, while the d i s s i p a t i o n h a l f - l i f e for carbaryl from the skin of adult males was 40.6 hr. Thiodicarb dissipated at an i n i t i a l rate (0-24 hr; t 1/2, α phase) of 40 hr from the skin of adult females and at a f i n a l rate (24-168 hr; t 1/2, 3 phase) of 254 h r . Surface, Penetrated, and Bound Residues. The time-course recoveries of [ l ^ C j l a b e l e d p a r a t h i o n , c a r b a r y l , and t h i o d i c a r b from s k i n (surface, penetrated, and bound residues) o f adult rats expressed i n percentage o f residual pesticide are given i n Table I. During the f i r s t 24 hr following topical application, 94 to 98% of the applied parathion remained on the surface of the skin. Small quantities of parathion penetrated the skin (1.6 to 5.6%) and were available f o r absorption into blood. Less than 0.3% of the parathion in the skin was present as bound residues. In the case o f carbaryl, 74 to 94% o f the t o p i c a l l y applied dose was found on the surface o f Jjie skin over a period of 72 hr. The percentage of penetrated [ C] increased with time along with the percentage of bound residues. Topically applied thiodicarb largely remained on the surface o f the skin during the study. A small percentage (3.0 to 10%) o f thiodicarb penetrated tljig skin. Bound residues varied between 0.4 and 3.1% of residual [ C] thiodicarb equivalents. ^ The t o t a l amount of [ C ] l a b e l e d p a r a t h i o n , c a r b a r y l , and thiodicarb equivalents present i n ug and percentage of dose i s given in Table I I . Carbaryl, parathion, and thiodicarb reached plateau values of 35, 17, and 7 ug^respectively, per treated area of skin. Absorption vs Dissipation. The r e l a t i o n s h i p between the loss of the t o p i c a l l y applied dose of parathion, carbaryl, and thiodicarb and the absorbed dose i s given i n Figures 6 and 7. The regression lines showed that the absorbed dose was considerably less than the dose l o s t from s k i n . The skin loss data correlated well with the absorp tion data. Simultaneous Absorption and Elimination i n Plasma. The tjme-concen trât ion curves f o r the absorption and elimination of [ C] labeled parathion, carbaryl, and thiodicarb equivalents i n plasma o f adult rats are g i v e ^ i n Figure 8 and the pharmacokinetic constants i n Table III. The [ C]equivalents were found i n blood shortly after the application of the dose and reached maximum concentrations i n plasma i n 2.5 to 12 h r . C a r b a r y l and p a r a t ^ o n [ C] e q u i v a l e n t s were e l i m i n a t e d during the study, while [ C ] t h i o d i c a r b e q u i v a l e n t s


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ffi O H < J - O O C N < t O O C M v D O < t O O ^HCM.ONCM) c o n c e r n i n g "safe" working conditions. N o n t e c h n i c a l Summary The e f f e c t o f a t o p i c a l l y a p p l i e d dose o f p a r a t h i o n , c a r b a r y l , and t h i o d i c a r b on r e d b l o o d c e l l c h o l i n e s t e r a s e a c t i v i t y i n t h e r a t was reviewed a l o n g w i t h p h a r m a c o k i n e c t i c d a t a d e v e l o p e d on t h e i r p e r c u taneous a b s o r p t i o n . P a r a t h i o n and t h i o d i c a r b i n h i b i t e d 50% o f the red c e l l c h o l i n e s t e r a s e a c t i v i t y at dose l e v e l s o f 3.2 and 33 mg/kg o f bw, w h i l e no i n h i b i t i o n was d e t e c t e d w i t h c a r b a r y l at dose l e v e l s as h i g h as 417 mg/kg o f ^>w. P a r a t h i o n and c a r b a r y l were absorbed a t 0.33 and 0.18 ug/hr/cm , while t h i o d i c a r b was absorbed a t rates v a r y i n g from 0.27 to 0.042 u g / h r / c m o f s k i n . S k i n l o s s and plasma e l i m i n a t i o n d a t a were used to c a l c u l a t e the v a l u e s . The t o p i c a l l y a p p l i e d p e s t i c i d e s slowly penetrated s k i n and were a v a i l a b l e for a b s o r p t i o n i n t o b l o o d and r e d i s t r i b u t i o n t o o t h e r t i s s u e s . Recovery d a t a suggested t h a t e v a p o r a t i v e l o s s e s o c c u r r e d d u r i n g the c o u r s e o f the 5-day s t u d y . The p e s t i c i d e s may be removed from s k i n by w a s h i n g , thus r e d u c i n g t h e amount a v a i l a b l e f o r a b s o r p t i o n . Acknowledgments The a u t h o r s wish to thank K a r i n Yee and C r a i g Ackerman f o r t h e i r a s s i s t a n c e i n t h e s e s t u d i e s and U n i o n Carbide A g r i c u l t u r a l P r o d u c t s Company, Inc., for support and [ C]labeled carbaryl and thiodicarb.

Literature Cited 1. Knaak, J. B.; Jackson, T.; Fredrickson, A. S ; Maddy, K. T.; Akesson, Ν. B. Arch. Environm. Contam. Toxicol. 1976, 9, 217-229.



5.

K N A A K A N D WILSON

Dermal

Dose-Cholinesterase

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