Dermal Exposure Related to Pesticide Use - ACS Publications

31 Occupational Exposure to Pesticides and Its Role in Risk Assessment Procedures Used in Canada CLAIRE A. FRANKLIN

Downloaded by COLUMBIA UNIV on March 9, 2013 | http://pubs.acs.org Publication Date: February 25, 1985 | doi: 10.1021/bk-1985-0273.ch031

Environmental Health Directorate, Department of National Health and Welfare, Ottawa, Ontario, Canada K1A 0L2

The process whereby pesticides are registered in Canada is not unlike that in many other countries. The manufacturer is required under Federal law to submit, at the time of application for registration, a package of data supporting the safety and efficacy of the product. If after review of these data, the product is judged to be acceptable, it is registered and food tolerances are established if required. Over the past 5 years there has been an increased awareness of the potential health hazards to those involved in the application of pesticides and those inadvertently exposed during application (bystanders). To properly analyze these risks, more accurate estimates of exposure are essential. The problems associated with current methods of exposure, the importance of analysis of urinary metabolites, the correlation of dermal exposure and urinary metabolites and the determination of percutaneous penetration are discussed. In most developed nations, the sale and use of pesticides are regulated through l e g i s l a t i o n . In Canada, the primary l e g i s l a t i o n under which pesticides must be registered before they can be l e g a l l y sold i s the Pest Control Products Act. This Act is administered by the Department of A g r i c u l t u r e , and numerous other departments and agencies are requested to provide advice to Agriculture before a regulatory decision i s made on any product. The Department of National Health and Welfare advises on a l l human health related matters and, under the provisions of the Food and Drugs Act and Regulations, maximum residue l i m i t s are set where appropriate. The assessment of potential human health hazards resulting from the use of pesticides requires knowledge of both the amount of exposure to the person and the inherent t o x i c i t y of the product. Whereas there has been considerable effort i n the past to monitor pesticide residues l e f t on food after normal a g r i c u l t u r a l usage, i t 0097-6156/85/0273-0429$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.


430

DERMAL EXPOSURE RELATED TO PESTICIDE USE

i s only i n recent years that regulatory agencies have emphasized the need to quantitatively assess the amount of pesticide to which the applicator i s exposed. There are many other situations i n which a potential human exposure exists occupâtionally i n the manufacture, formulation and domestic or commercial application of pesticides and inadvertently for bystanders i n or near sprayed areas. Although the potential human exposure may be highest i n the manufacture and formulation of the technical pesticide, i t i s also feasible that technological controls can be implemented to minimize exposure. However, once the pesticide i s available i n the open market, control of exposure becomes the r e s p o n s i b i l i t y of the i n d i v i d u a l user. Since there i s a wide range of expertise i n handling the products, i t i s essential that there be a wide enough margin of safety to encompass the anticipated excursions above normal i n levels of exposure. Eight of the ten provinces i n Canada have licencing procedures for commercial pesticide applicators. This s i t u a t i o n i s currently being re-evaluated and the f e a s i b i l i t y of developing a core program and reciprocal licencing i s being discussed. At the present time there are no provisions i n any of the provinces to licence farmers. However, the implemention of some type of training and c e r t i f i c a t i o n program for farmers i s also being considered. Steps i n Risk Assessment The process whereby the risks associated with the use of pesticides are assessed has become increasingly complex over the years, and even the d e f i n i t i o n of the term r i s k assessment i s widely variable. However, most include the concepts of hazard and probability of occurrence and require information on toxicology and exposure. In the i d e a l s i t u a t i o n (Table I ) there should be accurate data on the actual amount of pesticide to which the worker was exposed (including the primary route of exposure), the absorption should be known (enabling correction of the exposure estimate) and there should be a well defined no e f f e c t l e v e l (NOEL), preferably derived from a study i n which the route of exposure was similar to that i n man. These data would enable a r e a l i s t i c calculation to be made of the margin of safety (MOS). In the case of non-threshold effects, there should be adequate data to allow a quantitative risk estimate to be calculated using suitable s t a t i s t i c a l models. The remaining step would be to determine the a c c e p t a b i l i t y of the margin of safety. I f the margin were unacceptable, steps would then have to be taken to determine the r i s k management strategy that would reduce or eliminate the r i s k . Unfortunately, i d e a l conditions do not p r e v a i l , and the variance i n each of these components can have a profound effect on the v a l i d i t y of the r i s k estimation as discussed below. Exposure Estimate. Although considerable e f f o r t has been expended in the characterization of t o x i c i t y , there has not been an equivalent e f f o r t directed towards systematically estimating human exposure following use of these products. I t has been shown that the dermal route of exposure i s predominant i n many types of


31.

FRANKLIN

Occupational

Table I.

Pesticide

Exposure

in

Canada

431

Proposed Steps i n Risk Assessment RISK ASSESSMENT

Exposure Estimate Dermal/Inhalation Absorption Correction Estimated Dosage NOEL from Toxicity Data


Margin of Safety

β

NOEL or Exposure

Quantitative Risk Assessment

Acceptability of Margin RISK MANAGEMENT STRATEGIES Minimization of Exposure -

closed systems personal protective clothing formulation equipment education, training, licensing r e s t r i c t i o n of uses cancellation/suspension

application (1^) and h i s t o r i c a l l y , absorbent patches have been u t i l i z e d to estimate the amount of pesticide which impinges on the skin. Durham and Wolfe ( 2 ) developed the technique of placing patches at points close to the body parte which would come i n direct contact with the pesticide. This resulted i n regional patch deposition densities being used to calculate deposition to the face, V of chest, back of neck, lower arms and hands. The problems associated with the assumptions of the patch technique have been discussed elsewhere ( 3 ) . Regardless of these problems, the patch technique has gained acceptance as an indicator of dermal exposure, and this i s reflected i n the number of published studies using the technique (4.>.5>6)· One of the obvious advantages of the patch technique i s that i t i s non-invasive and i s adaptable to any use situation. Unfortunately there i s a wide range i n the exposure values reported i n the l i t e r a t u r e even i n studies where similar application techniques were used (Table I I ) . More recent studies, and especially those submitted i n support of new registrations, exhibit a wide variation i n the location and number of patches used to measure impingement on different body parts and i n the method for determining exposure. Closer analysis of these studies must be carried out before a "standardized" protocol i s adopted. I t remains to be determined whether the variations seen are due to true variations i n exposure (due to personal handling differences, formulation type or wind) or whether they simply r e f l e c t differences i n the method of calculation of the data.


432


Table I I .

Summary of Published Studies on P o t e n t i a l


Exposure of Workers U s i n g A i r B l a s t Equipment from P a t c h Data and Hand Swabs or Hand Washes (6)

References

Pesticide

Jegier (1964) Jegier (1964) Simpson (1965) Jegier (1964) Jegier (1964) Simpson (1965) Jegier (1964) Wolfe (1967) Wolfe (1967) Wojeck (1982) Batchelor (1954) Wojeck (1981) Wassermann (1963) Wassermann (1963)

parathion malathion azinphosmethyl az inphosmethy1 parathion carbaryl carbaryl az inphosmethy1 malathion arsenic parathion ethion azinphosmethyl azinphosmethyl

Dermal Exposure mg*hr"l 2.4 2.5 9.9 12.9 19.0 24.9 25.3 27.2 30.0 68.0 77.7 288.0 541.0 755.0

It has been suggested that c o r r e l a t i o n of exposure with the amount of pesticide applied rather than with the time taken to complete the application would reduce the v a r i a b i l i t y , p a r t i c u l a r l y i n operations which might take some applicators considerably longer to complete than others. There i s also considerable v a r i a t i o n between studies i n the placement of patches and whether or not hand washes are included i n the estimate. The r e l i a b i l i t y of patch data to estimate actual exposure i s questionable. Body areas such as hands and face are extremely d i f f i c u l t to patch yet are probably the most highly contaminated areas. Some studies do not include any patches under the clothing, yet i t has been shown on many occasions that pesticides may permeate clothing or enter through garment openings. Early studies done with fluorescent markers c l e a r l y showed this was true and also that the hands and face were highly exposed (JJ · Only recently has the problem of the loss of pesticide from patches used i n the f i e l d been addressed (8). Many studies do not report laboratory or f i e l d recovery data for sampling substrates or comment on correction for recovery of the data (9). Serat (8) found that cotton gauze retained only 30% of extractable parathion and 70% of extractable d i c o f o l under f i e l d conditions. He concluded that i n the absence of adequate controls to determine the quantity of chemical lost from the fabric c o l l e c t o r s there i s no assurance that the extracted depositions represent anywhere near the actual values. This factor seriously l i m i t s the usefulness of many older exposure studies. New techniques using fluorescent markers (10) are promising and w i l l undoubtedly lead to more quantitative estimates of contact exposure.


31.

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Occupational

Pesticide

Exposure

in

Canada

433


Another practice which may result i n a large difference i n the exposure estimate i s the extrapolation of data collected for a portion of the spray operation to that of a f u l l day. This needs to be more f u l l y investigated because of the trend to conduct studies for one hour and then to extrapolate to 8 hours. Measurement of hand exposure. This measurement alone can have a tremendous effect on the exposure estimate. Three techniques are used to estimate hand exposure: wrist patches, cotton gloves and hand washes. The use of cotton gloves has been c r i t i c i z e d as unduly overestimating hand exposure due to absorption of l i q u i d s . It is also apparent that extrapolation from a wrist patch to hand exposure would underestimate exposure. Swabbing or washing have been suggested as alternatives (11). Davis (11) compared hand exposures of apple thinners using gloves and hand washes. He found that hand exposures obtained by r i n s i n g were s i g n i f i c a n t l y lower than those obtained by using either cotton or nylon gloves. The mean exposures for cotton or nylon gloves were approximately 4-5 times larger than those obtained by using hand rinses. Davis concluded that the use of gloves to monitor hand exposure grossly exaggerates estimates of t o t a l potential exposure. However, hand washes measure that pesticide which has not been absorbed or i s not i r r e v e r s i b l y bound i n the layers of the skin. I t has been found that regardless of solvent rinsings, pesticides can remain on the skin for long periods of time (12). The true value for hand exposure probably l i e s somewhere between the two measurements. Studies showing the portion of dermal exposure that has been attributed to the hands are summarized i n Table I I I . Regardless of the method used to measure hand exposure these studies show that the hands contribute from 27% to 99% of the t o t a l dermal exposure. In mixer/loader situations where the worker i s more l i k e l y to contact the concentrate, the majority of dermal exposure i s to the hands regardless of whether extra protective gloves were worn over the cotton gloves or a closed mixing system was used. Wojeck (13) used eight outside patches and the palms and back of cotton gloves to estimate t o t a l dermal exposure to mixer/loaders or a i r b l a s t applicators of ethion. Mixer/loaders received 76% of the t o t a l dermal exposure to the hands and applicators received 42% of the t o t a l dermal exposure to the hands. I f the o r i g i n a l patch method of Durham and Wolfe (2), which did not include a hand exposure estimate i s used to recalculate the data, the t o t a l dermal estimate, was 10 times lower than the t o t a l body method used by Wojeck. This emphasizes the importance of using hand exposures to more accurately estimate t o t a l exposure. In another study using the same method, Wojeck (14) measured exposure of mixer/loaders and a i r b l a s t applicators using arsenic spray. Hand exposure accounted for 52% and 41% of t o t a l dermal exposure for mixer/loaders and applicators respectively. In several studies carried out during a e r i a l a g r i c u l t u r a l applications, a large portion of the t o t a l exposure was also seen on the hands, especially for mixer/loaders. Peoples (15) monitored the p o t e n t i a l dermal and inhalation exposure of mixer/loaders, p i l o t s



benomyl (W.P.)

diallate (E.C.)

Everhart (1981)

Ground Dubelman (1982)

open

cotton gloves

41

52

open

closed

cotton gloves*

not sampled

n.d.

99

-

64

-

-

-

-

96

open

cotton gloves*

cotton gloves

27

-

74

closed

handwash*

73

-

—

-

-

42

41

-

Flagger (%)

n.d. not detected

Pilot (%)

57

-

42

Applicator (%)

76

Mixer/Loader (%)

closed

handwash*

open

Mixing System

cotton gloves

Method

Hand Exposure (% of t o t a l )

5

1

-

"-

-

0.01

1

Respiratory Exposure (% of total)

Hand Exposure Expressed as a Percentage of T o t a l Dermal Exposure

workers wore protective gloves

mevinphos (E.C.)

Maddy (1982)

*

DEF (E.C.)

lead arsenate (liquid)

ethion (E.C.)

Aerial Peoples (1979)

Wojeck (1982)

Orchard Wojeck (1981)

Pesticide

Table I I I .



31.

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Occupational

Pesticide

Exposure

in

Canada

435

and flaggers during the performance of duties associated with the a e r i a l application of DEF. Multi-layered patches were attached to seven body areas i n such a way that estimates of deposition exposure to exposed areas and clothed areas could be calculated. Hand exposure was measured using a hand wash and accounted for 57% of the t o t a l dermal exposure. I t i s l i k e l y that hand exposure was reduced i n this study for mixers by the provision of a closed mixing system and the use of neoprene gloves. Surprisingly the p i l o t received 73% of his dermal exposure to the hands. The authors attributed this to the p i l o t s adjusting nozzles of the a i r c r a f t without using the required protective gloves. I t should be noted that good f i e l d observations are valuable i n some cases to explain unusual values. Also, i f hand exposure had been based on extrapolation from lower wrist patches such unexpected but important exposures might have been missed. The flagger received only 42% of the dermal exposure on the hands. As flaggers are exposed to the airborne spray cloud, other areas such as the head and shoulders become more important areas for pesticide deposition. Maddy (16) monitored dermal and inhalation exposures f o r mixer/loaders, flaggers and p i l o t s associated with the a e r i a l application of mevinphos, using the methods described i n Peoples (15). In this study the mixer/loaders operating closed transfer systems wore gloves but others associated with the spray operation did not. The mixer/loaders received 74% of their t o t a l dermal exposure on the hands, flaggers received 42% and p i l o t s received 27%. P i l o t s received a considerably lower proportion of the t o t a l exposure to the hands than i n the study by Peoples (15). The use of closed systems did not appear to modify the proportion of the t o t a l exposure that occurred on the hands i n either a e r i a l studies or i n the orchard studies. However i t i s premature to draw conclusions r e l a t i v e to the s u i t a b i l i t y of closed systems. This i s an important area to be considered for reduction of exposure and more studies on the magnitude of reduction would be very useful. Everhart (17) monitored 8 mixer/loaders who each prepared one tankful of benomyl for a e r i a l application. Five gauze pads and cotton gloves were used to measure exposure. Most workers wore additional protective gloves over the cotton gloves. Regardless of t h i s additional precaution 96% of the t o t a l dermal exposure was found on the cotton gloves. In almost a l l other cases the forearm patches had the highest levels of contamination. In a different use s i t u a t i o n Dubelman (18) measured dermal and inhalation exposure to mixer/loaders and applicators associated with the boom application of the herbicide d i a l l a t e . The body was patched at 5 locations for the 6 open mixing t r i a l s and 12 locations for the 9 closed mixing t r i a l s . Hand exposure was measured using cotton gloves. For the closed mixing t r i a l s neoprene gloves were worn over the cotton gloves but no additional gloves were worn during the open system mixing t r i a l s . In the open mixing t r i a l s hand exposure for the mixer/loaders accounted for 99% of the t o t a l exposure. In the closed mixing t r i a l s no hand exposure was detected and i n fact t o t a l dermal exposure was reduced to less than 1% of that found during open mixing. I t cannot be ascertained whether this exposure reduction was due to the closed system or to the use


436



of the neoprene gloves. The applicators were observed to have 64% of the t o t a l dermal exposure on their hands. Although various patch techniques were used as w e l l as d i f f e r e n t methods of estimating hand exposure i n these studies, they a l l emphasize the importance of including an estimate of hand exposure i n calculating the t o t a l dermal exposure. The available data do not c l e a r l y indicate which procedure for estimation of hand exposure i s the most accurate. Since i t has been suggested that cotton gloves overestimate hand exposure i t would be prudent from the point of view of health protection to use this method u n t i l better methods are designed. Metabolite Analyses. The current d i f f i c u l t i e s surrounding the use of patch data to quantitatively estimate exposure have led to the development of alternative methods such as the measurement of urinary metabolite l e v e l s . S t u d i e s i n which both u r i n a r y metabolites have been measured and patches analyzed have emphasized the u n r e l i a b i l i t y of patches (.3,7^2.)· Unfortunately there are also difficulties i n using metabolite excretion as a quantitative indicator of exposure, and i t i s essential that consecutive 24 hour urine samples be taken (7^). F a i l u r e to do so results i n a lack of c o r r e l a t i o n between metabolite excretion and patch data (13). The c o l l e c t i o n of accurate 24 hour samples over several days requires the coopérators to be highly motivated, and this i s a major problem with this method. The detection of pesticide metabolites i n the urine of workers indicates prior exposure. However, i t i s d i f f i c u l t to relate this l e v e l of urinary metabolite to the actual worker exposure, and i t i s equally d i f f i c u l t to interpret the t o x i c o l o g i c a l significance of the level. A preliminary study conducted i n rats exposed dermally to 100, 200 and 400 ug of azinphos-methyl showed a s i g n i f i c a n t linear c o r r e l a t i o n between the dermal dosage and the urinary a l k y l phosphate metabolite levels (19). Further studies are being conducted i n other species to determine whether a similar type of relationship occurs and to develop a standard curve i n which urinary metabolite levels could be u t i l i z e d to estimate the amount of dermal exposure. Exposure Studies. Although submission of applicator exposure studies (or s u i t a b l e exposure e s t i m a t e s ) are c u r r e n t l y a r e g i s t r a t i o n requirement i n Canada, i t i s our intention to ascertain whether exposure scenarios can be developed to provide a "worst case" or maximum expected exposure l e v e l . Considerable e f f o r t has gone into the development of a forestry scenario (20,21) i n which the estimated exposure levels appear to be comparable to those observed i n actual f i e l d studies (22). Whether other scenarios can be developed and validated i s currently being evaluated i n a collaborative venture between industry and government. Dermal/Inhalation Absorption Correction. Since i t i s generally presumed that 100% of the inhaled pesticide dose i s absorbed, l i t t l e work i s being done to refine t h i s . I t has also been shown that i n most a g r i c u l t u r a l applicators the dermal route i s the predominant route of exposure. However, the patch methods which are used only



31.

FRANKLIN

Occupational

Pesticide

Exposure

in

437

Canada

estimate the amount of pesticide which impinges on the skin and do not give any indication of the actual amount absorbed (the p o t e n t i a l l y toxic dosage). This i n i t s e l f would not pose as large a a problem i f the predictive t o x i c i t y data were generated using the dermal route of exposure, but this i s not generally the case. Therefore, due to the wide variations i n the absorption of various pesticides (23), the contact dosage should be corrected by the actual absorption of the pesticide i n question. The use of percutaneous penetration data to correct dermal exposure estimates i s i n i t s infancy, and there are numerous aspects which must be investigated before this becomes an accepted regulatory procedure. I t has been shown that there i s species v a r i a b i l i t y i n percutaneous penetration and that the skin of miniature pigs and rhesus monkeys most closely estimate absorption i n man (23). The s i t e of application (24), single versus multiple exposure (25,26) and environmental factors such as temperature, humidity, l i g h t and a i r flow also affect penetration. Work i n my laboratory using l a b e l l e d Guthion (azinphos-methyl) according to the method of Maibach, i n which a correction factor for incomplete urinary excretion of the pesticide i s applied to the dermally administered dosage, confirms these e a r l i e r findings (Table IV). Technical Guthion was t o t a l l y absorbed i n both rats and rabbits and less than

14

Table IV.

Percutaneous Penetration of C-Guthion Expressed as % of Applied Dose

(azinphos-methyl)

Compound

Rat

Rabbit

Rhesus Monkey

Guthion i n propylene glycol

50.0+14(IM)

31.7+5(IM)

70.4+2(IM)

Guthion i n acetone

107.0+11(D)* 116.0+38(D)* (36 h)** (7 h)

47.4+10(F)* (23 h)

Man

36.1+11(F)' (31 h)

32.0+9 (A) (23 h) Guthion in H 0 2

W.P.

82.8+27(F) (27 h) 39.9+4 (A) (26 h)

IM intramuscular D intrascapular dermal F forehead dermal A forearm dermal *corrected for incomplete urinary excretion **t\ - excretion h a l f - l i f e



438


50% absorbed i n monkeys and man (Table IV). There was greater penetration from the forehead (47%) than the forearm (32%) i n monkeys although the difference was not as large as seen with other products which are currently being tested. These data suggest that the best predictor for man i s the monkey and that for this p a r t i c u l a r product either the forearm or forehead would give a reasonable estimate of absorption. Derivatization of the Guthion to the wettable powder increased penetration from the forehead but was without effect on the forearm. The wettable powder was applied as a suspension i n water which may account for the differences or simply emphasize the r e a l differences between application s i t e s . The wettable powder i s currently being tested i n man to see i f a similar e f f e c t occurs. Another parameter which varied amongst species was the excretion h a l f - l i f e with a much more rapid excretion i n rabbits (7 h) than i n monkeys (23 h), man (31 h) or rats (36 h). There has been increased emphasis on the development of i n v i t r o models to estimate absorption. These models have the advantages of being faster and less expensive than i n vivo models but w i l l require p a r a l l e l i n vivo studies to validate their s u i t a b i l i t y for estimating human absorption of pesticides. At the present time we assume that a l l of the pesticide which impinges on the skin as estimated i n the exposure study i s absorbed unless there are acceptable data which allow a s p e c i f i c correction to be made. Although i n many instances the correction of the exposure data does not s i g n i f i c a n t l y a l t e r the r i s k estimate, i t can become an important factor i n the cases of high exposure and/or high t o x i c i t y . I t i s therefore important that we have r e l i a b l e and accurate estimates of the amount of pesticide absorbed. One additional sequela of the dermal penetration studies on formulations i s that information may be gained which would prove useful i n designing products which are not well absorbed by humans. No Observed E f f e c t Level (NOEL) from Toxicity Data. The types of t o x i c i t y studies that are submitted i n support of r e g i s t r a t i o n are s i m i l a r throughout the world. In Canada there are no s p e c i f i c protocols delineated for the conduct of t o x i c i t y tests but most comply with those set under FIFRA, WHO, or OECD guidelines. The data requirements include the tests outlined on Tables V, VI, and VII. These are guidelines, not r i g i d requirements, and the manufacturers are encouraged to discuss their data packages before completion. One of the primary shortcomings of the standard data package with regard to worker/bystander r i s k assessment as i t exists today i s the emphasis on the o r a l route of exposure. Others are the limited data on k i n e t i c s of the chemical, lack of attention to determining the effect of the route of exposure on t o x i c i t y and the i n a b i l i t y to test combinations of pesticides i n a manner which would approximate the type of mixed exposure that applicators receive. These issues complicate the r i s k assessments for applicators, for whom the primary route of exposure i s dermal and generally i s intermittent. Risk Estimation. For pesticides which exert t o x i c o l o g i c a l effects that demonstrate a no observed effect l e v e l (NOEL), the standard


Occupational

FRANKLIN

Table V.

Pesticide

Exposure

in

Canada

Acute T o x i c i t y Tests Required for Registration (Technical and Formulations)

LD50 - o r a l , dermal, inhalation I r r i t a t i o n - dermal, eye Sensitization


Delayed neurotoxicity

Table VI.

Subacute T o x i c i t y Tests Required f o r Registration (Technical and Formulations)

90 day o r a l (rat and 12 month oral

dog)

(dog)

90 day dermal 90 day inhalation Delayed neurotoxicity ( i f acute test p o s i t i v e )

Table VII.

Long Term and Special Tests Required f o r Registration (Technical)

Chronic feeding (rat) Oncogenicity (rat and mouse) Pharmacokinetic

(appropriate routes)

Mutagenicity Teratology Multi-generation reproduction Exposure




440

procedure f o r r i s k estimation i s to use "safety" factors. This approach has been developed over a number of years, and one chapter i n an early Food and Drug Administration (FDA) publication addressed the issue of safety evaluation (27). The recommendations on the use of safety factors by the Food Protection Committee of the National Research C o u n c i l (28) were adopted by the J o i n t Food and A g r i c u l t u r a l Organization and World Health Organization Expert Committees on Food Additives (29) and Pesticide Residues (30). In addition to the one hundred fold safety factor suggested by Lehman (31), safety factors ranging to 5000 are used dependent upon a number of factors, including the severity of the t o x i c o l o g i c a l lesion, quality of the data base and sample s i z e . For pesticides which have been shown to be animal carcinogens, the r i s k estimation becomes more complicated, relying heavily upon s t a t i s t i c a l models which express the probability of occurrence as a function of dose. A l l of the s t a t i s t i c a l models need an exposure estimate expressed as a daily dosage to enable comparison with the exposure estimate from the chronic study. I f exposure to the population under study occurs on a daily l i f e t i m e basis, the procedure i s r e l a t i v e l y straight forward. However, i n many a g r i c u l t u r a l use situations the exposure to the applicator or bystander i s intermittent. In most cases there may be only a few days of exposure a year but i n some there may be more frequent exposure over the entire year. One approach that has been taken to obtain a l i f e t i m e daily exposure under these circumstances has been to conduct a worker f i e l d study and measure the exposure received f o r one day. This i s multiplied by the number of days worked i n a year and then by the number of working years. This i s an Amortized Daily Exposure. AMORTIZED EXPOSURE (ug/kg BW/day) = dosage* χ application rate χ acres treated χ duration working lifespan (days) This approach results i n a very small estimated daily exposure and ignores the t o x i c o l o g i c a l significance of high pulses of exposure. There are generally no toxicology data to support this approach. In the absence of these supporting data i t would be more prudent to assume the worst case; that i s the dosage as determined from the exposure study would be received every day for the working l i f e t i m e of the applicator. This i s a Peak Exposure. PEAK EXPOSURE (ug/kg BW/day) s

dosage* χ application rate χ acres treated

*dosage (ug/kg BW/lb a i ) = corrected dermal exposure + corrected inhalation exposure body weight (kg) χ a i applied (lb) I t i s obvious that this peak exposure approach i s also not the true case, and i f quantitative r i s k assessment i s to be feasible this very serious impediment w i l l have to be r e c t i f i e d through experi-



31.

FRANKLIN

Occupational

Pesticide

Exposure

in

441

Canada

ments designed to elucidate both the mechanism of action and the e f f e c t of intermittent exposure. The decision to use an amortized exposure value or a peak exposure value has a profound impact on the outcome of the quantitative r i s k assessment. To i l l u s t r a t e this point, data from an actual f i e l d exposure study were used. The average daily dermal exposure l e v e l as measured by the patch technique was used to calculate the amortized exposure l e v e l and the peak exposure l e v e l (Table VIII). Estimates of r i s k at low doses were obtained using l i n e a r extrapolation from the 1% excess r i s k point based on a f i t t e d Weibull model (32) and the Armitage-Doll multi-stage model (33). While both models gave similar results, the effect of the exposure estimates had a dramatic effect on the r i s k estimates. The amortized exposure estimates lowered the estimates of risk substantially. The shortcomings pertaining to the estimation of exposure which have been described are very serious, and these issues w i l l have to be resolved before s t a t i s t i c a l r i s k assessment models can be u t i l i z e d as the basis for regulatory decisions on the r e g i s t r a t i o n of pesticides.

Table VIII.

Effect of Exposure Level on Quantitative Risk Assessment

95% Upper Confidence Limit on Excess Risk Model

Amortized Exposure (mg/kg/da) 6

3xl0~ * Linear Extrapolation based on a f i t t e d Weibull Model

l.OxHT

Multi-stage Model

1.3xl0~

8

8

8xl0"

0.2*

5

2.7xl0"

3.6xl0~

Peak Exposure (mg/kg/da)

7

7

2.75

7.3xl0~

9.5xl0"

4

4

9.3xl0~

1.2xl0-

:

2

*Workers wore protective rubber gloves

Conclusion The estimate of exposure to workers involved i n the application of pesticides and to bystanders i s a c r i t i c a l component of r i s k assessment. The deficiencies of existing methods need to be r e c t i f i e d to ensure r e l i a b l e and accurate estimates of actual exposure. Emphasis should be placed on development of novel methods as well to a s s i s t i n assessing exposure. One of the more serious impediments to the use of quantitative risk assessment models i s the r e s o l u t i o n of the problem of exposure e s t i m a t i o n f o l l o w i n g intermittent exposure.


442



Nontechnical Summary The process whereby the risks associated with the use of pesticides are assessed has become increasingly complex over the years, and even the d e f i n i t i o n of the term risk assessment i s widely variable. However, most include the concepts of hazard and probability of occurrence and require information on toxicology and exposure. In the i d e a l s i t u a t i o n there should be accurate data on the actual amount of pesticide to which the worker was exposed, including the primary route of exposure, the absorption should be known, enabling correction of the exposure estimate, and the amount of pesticide necessary to cause toxic effects i n test animals should be known. From these data, i t could be determined whether the product could be used safely. Given that the margin between exposure to humans and the l e v e l which was toxic i n animals was unacceptable, steps would then have to be taken to determine the r i s k management strategy that would reduce or eliminate the r i s k . Unfortunately the i d e a l s i t u a t i o n does not exist and there are many d i f f i c u l t i e s which must be overcome before accurate r i s k assessments can be conducted. For pesticide applicators, the dermal route has been shown to be the most important one. However, the methods used to measure the amount of pesticide landing on the skin are not very r e l i a b l e and many studies conducted i n the past did not try to estimate hand exposure. This omission i s a serious one because i t has been shown that a very large percentage of the t o t a l dermal exposure i s to the hands. New methods using fluorescent tracer techniques are promising and w i l l undoubtedly lead to more quantitative estimates of contact exposure. A d e f i n i t e shortcoming of a l l of these existing techniques for measuring exposure i s that they measure the amount of pesticide that lands on the skin (contact exposure) and give no estimation of the actual amount of pesticide that i s absorbed through the skin. I t i s t h i s absorbed dosage which i s p o t e n t i a l l y toxic to a target tissue. There are many factors which must be considered when conducting absorption studies, including s i t e of application such as forehead or forearm, solvent or formulation and the actual pesticide i t s e l f . The effects of these parameters must be more f u l l y understood before correction of contact dosage can be done with certainty. Another way to estimate exposure i s to measure urinary metabolite l e v e l s . However, i t i s d i f f i c u l t to relate this l e v e l to the actual amount which contacted the skin and work i s currently underway to elucidate this relationship. Another factor which complicates the r i s k assessment i s the intermittent nature of pesticide exposure to applicators who may only use a s p e c i f i c product for a few days a year. Resolution of these issues i s essential i f we are to be able to s c i e n t i f i c a l l y support quantitative r i s k assessment. Acknowledgment s

The author wishes to thank Nancy Muir for her invaluable assistance i n preparing the manuscript and Linda Bradley who typed i t .


31.

FRANKLIN

Occupational

Pesticide

Exposure

in

Canada

443

Literature Cited 1. 2. 3. 4.


5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23.

Durham, W.F.; Wolfe, H.R.; Elliot, J.W. Arch. Environ. Health. 1972, 24, 381-387. Durham, W.F.; Wolfe, H.R. Bull. WHO 1962, 26, 75-92. Franklin, C.A.; Muir, N.I.; Greenhalgh, R. in Pesticide Residues and Exposure, ACS Symposium Series 182, 1982, p. 157-168. Nigg, H.N.; Stamper, J.H. Arch. Environ. Contam. Toxicol. 1983, 12, 477-482. Atallah, Y.H.; Cahill, W.P., Whitacre; D.M. Arch. Environ. Contam. Toxicol. 1982, 11, 219-225. Wolfe, H.R.; Durham, W.F.; Armstrong, J.F. Arch. Environ. Health. 1967, 14, 622-633. Franklin, C.A.; Fenske, R.A.; Greenhalgh, R.; Mathieu, L.; Denley, H.V.; Leffingwell, J.T.; Spear, R.C. J. Toxicol. Environ. Health. 1981, 7, 715-731. Serat, W.F.; VanLoon, A.J.; Serat, W.H. Arch. Environ. Contam. Toxicol. 1982, 11, 227-234. Lavy, T.L.,; Shepard, J.S.; Mattice, J.D. J. Agric. Food Chem. 1980, 28, 626-630. Fenske, R.A.; Leffingwell, J.T.; Spear, R.C. Presented at 184th ACS National Meeting, Kansas City, Mo, Sept. 1982. Davis, J.E.; Stevens, E.R.; Staiff, D.C. Bull. Environ. Contam. Toxicol. 1983, 31, 625-630. Kazen, C.; Bloomer, Α.; Welch, R.; Qudbier, Α.; Price, H. Arch. Environ. Health, 1974, 29, 315-318. Wojeck, G.A.; Nigg, H.N.; Stamper, J.H.; Bradway, D.E. Arch. Environ. Contam. Toxicol. 1981, 10, 725-735. Wojeck, G.A.; Nigg, H.N.; Braman, R.S.; Stamper, J.H.; Rouseff, R.L. Arch. Environ. Contam. Toxicol. 1982, 11, 661-667. Peoples, S.A.; Maddy, K.T.; Datta, P.R.; Johnston, L.; Smith, C.; Conrad, D.; Cooper, C. Calif. Dept. Food and Agr. Report HS-676, Nov. 1976, p. 34. Maddy, K.T.; Winter, C.; Cepello, S.; Fredrickson, A.S. Calif. Dept. of Food and Agr. Report HS-889, Jan. 1982, p. 34. Everhart, L.P.; Holt, R.F. J. Agric. Food Chem. 1982, 30, 222-227. Dubelman, S.; Lauer, R.; Arras, D.D.; Adams, S.A. J. Agric. Food Chem., 1982, 30, 528-532. Franklin, C.A.; Greenhalgh, R.; Maibach, H.I. in: IUPAC Pesticide Chemistry: "Human Welfare and the Environment," Pergamon Press, 1983; p. 221-225. Houghton, E.R. Standardized scenarios of pest control situations as a means of assessing human exposure to pesticides. Agriculture Canada, Ottawa, 1978. Crabbe, R.; Krzymien, M.; Elias, L.; Davie, S. National Research Council of Canada. Report No. LTR-UA-62, Part I, 1982. Franklin, C.A.; Muir, N.I. National Research Council of Canada, 1984, in press. Feldman, R.J.; Maibach, H.I. Toxicol. Appl. Pharmacol. 1974, 28, 126-132.


DERMAL


444

EXPOSURE

RELATED

TO

PESTICIDE

USE

24. Maibach, H.I.; Feldman, R.J.; Milby, T.H.; Serat, W.F.; Arch. Environ. Health. 1971, 23, 208-211. 25. Wester, R.C.; Noonan, P.K.; Maibach, H.I. Arch. Dermatol. Res. 1980, 267, 229-235. 26. Wester, R.C.; Noonan, P.K. Int. J. Pharm. 1980, 7, 99-110. 27. Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics. Association Food and Drug Officials of the United States (AFDOUS) 1959. 28. NRC/NAS (National Research Council/National Academy of Sciences) Food Protection Committee, Food and Nutrition Board. Evaluating the Safety of Food Chemicals Washington DC. NAS 1970. 29. Joint FAO/WHO Expert Committee on Food Additives, 1972. WHO Tech. Report Series 505. 30. Joint FAO/WHO Expert Committee on Pest. Residues, 1965. FAO Meet Rep. No. PL/1965/10, WHO/Food Add/26-65. 31. Lehman, A.J.; Fitzhugh, O.G. Assoc. Food Drug Officials Q. Bull. 1954, 18:33-35. 32. Krewski, D.; Van Ryzin, J . in Statistics and Related Topics, North-Holland Publishing Co. 1981, p. 201-231. 33. Howe, R.B.; Crump, K.S. Global 82: Report for Office of Carcinogen Standards, Dept. of Labour Contract YIUSC252C3. 1982. RECEIVED August 28, 1984


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