34 Assessment of Farmworker Risk from Organophosphate-Induced Delayed Neuropathy 1
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BARRY W. WILSON, MICHAEL HOOPER1, EDWARD CHOW, JAMES N. SEIBER, and JAMES Β. KNAAK Downloaded by UNIV ILLINOIS URBANA on March 8, 2013 | http://pubs.acs.org Publication Date: February 25, 1985 | doi: 10.1021/bk-1985-0273.ch034
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Department of Avian Sciences, University of California, Davis, CA 95616 Department of Environmental Toxicology, University of California, Davis, CA 95616 California Department of Food and Agriculture, Sacramento, CA 95814
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Organophosphate Induced Delayed Neuropathy (OPIDN) is an axonal neuropathy characterized by delayed onset, species and toxicant specificities. This paper discusses special features of OPIDN with regard to the workplace and the environment, body surfaces, metabolism, target cells and molecules, gene regulation and toxicity identification. Among the examples used is isofenphos, the active ingredient in the registered pesticide Oftanol; evidence regarding its neurotoxicity in hens at single doses of 100 mg/kg is reviewed. Reasons for the lack of recognition of its neuropathic potential in the past are discussed with respect to EPA regulations for screening for neuropathic organophosphorus esters. Organophosphate Induced Delayed Neuropathy (OPIDN) and other long-term problems of organophosphorus e s t e r (OP) a g r i c u l t u r a l chemicals pose special problems for r i s k assessment. Procedures have been developed over the years to evaluate the dangers from acute exposures to OPs, but the i n s i d i o u s e f f e c t s of repeated exposures to toxic chemicals are more d i f f i c u l t to anticipate and to detect. The acute effects of OPs are usually due to their i n h i b i t i o n of AChE at the motor end p l a t e s of the p e r i p h e r a l and the synapses of the central nervous systems. Unfortunately, OPIDN i s not related i n any simple way to these i n h i b i t i o n s . OPIDN i s an axonal neuropathy caused by some but not a l l OPs (1). It i s characterized by delayed onset, axonal destruction f o l l o w e d by m y e l i n degeneration and death of the nerve c e l l bodies i n the c e n t r a l nervous system (Table I). Sensitive animals i n c l u d e man, c a t , dog, sheep, water b u f f a l o and the chicken but not rodents. The chicken i s usually the experimental animal of choice. 0097-6156/85/0273-0479$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.
D E R M A L E X P O S U R E R E L A T E D TO PESTICIDE USE
480
Table I. S e l e c t e d Symptoms Of Organophosphorus Ester-Induced Delayed Neuropathy
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Early ( F i r s t few days) Inhibition of ΝΤΕ, a special carboxyesterase a c t i v i t y
Later ( F i r s t few weeks) Aggregation of neurotubules Axonal swelling proximal to d i s t a l nodes of Ranvier
S t i l l Later (Two-three weeks) Interruption of axoplasmic flow; axonal demyelination C e l l body damage i n brain and spinal cord Progressive ataxia and paralysis of lower limbs. Much Later (Months) Slow recovery of movement may occur. Agriculture has been fortunate to be r e l a t i v e l y free of mass outbreaks of OPIDN. The major chemical o f f e n d e r has been the p l a s t i c i z e r and l u b r i c a n t t r i - o r t h o - c r e s y l phosphate (TOCP). Contamination of v a r i o u s products w i t h TOCP has p a r a l y z e d thousands of people since the turn of the century (2). OPs i n use i n agriculture that have been shown to be neuropathic include the c o t t o n d e f o l i a n t DEF and the p e s t i c i d e s EPN, haloxon and leptophos (not r e g i s t e r e d i n the US). Neuropathic OPs used experimentally include DFP and mipafox; one nerve gas (sarin) has been shown to cause OPIDN and there i s evidence another (soman) i s also a delayed neuropathic agent (3). Recently, Wilson et a l . (4) found that isofenphos (IFP) caused OPIDN i n hens. EPA g u i d e l i n e s s p e c i f y a two-stage t e s t f o r i d e n t i f y i n g neuropathic OPs u s i n g l a y i n g hens (5,6). In the f i r s t step OPs are screened with a single acute dose (usually near the LD50) and observed for three weeks. If OPIDN appears, a 90 day subchronic repeated exposure study i s performed to determine a n o - e f f e c t l e v e l (NOEL). The cause of OPIDN i s unknown; there i s no cure. A s p e c i a l carboxyesterase enzyme test developed by Johnson (_7) q u a n t i f i e s the i n h i b i t i o n of the h y d r o l y s i s of phenyl v a l e r a t e due to a neuropathic OP that occurs i n addition to the i n h i b i t i o n i n the presence of a non-neuropathic OP. Although the e x i s t e n c e of a single enzyme corresponding to ΝΤΕ a c t i v i t y i s not u n i v e r s a l l y accepted (1), i n h i b i t i o n s of ΝΤΕ a c t i v i t y greater than 70-80% are f a i r l y r e l i a b l e p r e d i c t o r s of the appearance of OPIDN weeks l a t e r . ΝΤΕ a c t i v i t y i s e s p e c i a l l y high i n nervous t i s s u e and lymphocytes (8) and i t s i n h i b i t i o n i s thought by some to be the i n i t i a t i n g step i n the disorder (9). OPs are also known to damage muscles. Dettbarn and colleagues (10) propose that injury to skeletal muscle of rats brought about by p a r a t h i o n i s due to an excess of ACh at the neuromuscular j u n c t i o n . Not a l l muscles are s e v e r e l y damaged by the agent (perhaps no more than 10 per cent of the muscles are a f f e c t e d ) and the phenomenon has been mainly s t u d i e d i n rodents. I t i s
In Dermal Exposure Related to Pesticide Use; Honeycutt, R., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1985.
34.
WILSON ET AL.
Farmworker Risk from
481
OPIDN
important that i t be examined i n animals prone to OPIDN such as chickens, cats and man. There i s increasing concern but l i t t l e knowledge concerning s u b t l e e f f e c t s of OP's on behavior. One study of f i e l d workers poisoned badly enough by OPs to be hospitalized indicated that a memory d e f i c i t could be found as long as ten years a f t e r an episode (11).
Downloaded by UNIV ILLINOIS URBANA on March 8, 2013 | http://pubs.acs.org Publication Date: February 25, 1985 | doi: 10.1021/bk-1985-0273.ch034
Research Levels Research on a g r i c u l t u r a l chemicals f a l l s naturally into several c a t e g o r i e s r e f l e c t i n g the order of events that occur when a p e s t i c i d e i s used. The rows i n Table I I are a l i s t of a loose hierarchy of levels of pesticide action from environment to gene; the columns i n the table separate topics appropriate to research (factors) and r e g u l a t i o n ( a c t i o n s ) . D i f f e r e n t r e s e a r c h f a c t o r s and r e g u l a t o r y a c t i o n s are a s s o c i a t e d w i t h each l e v e l of o r g a n i z a t i o n . Each of these, environment, body surface, metabolism, c e l l s and molecules, and n u c l e i c a c i d s , present s p e c i a l f e a t u r e s . Although o u t s i d e the hierarchy of organization of l i v i n g systems, the major problem of i d e n t i f i c a t i o n of OPs that cause OPIDN i s a l s o i n c l u d e d i n the diagram.
Table I I .
Research and R e g u l a t i o n of Use of Organophosphorus Esters
Categories Workplace and Environment
Body Surfaces Metabolism
Factors Residues Reactions Who's at Risk?
Permeability Solubility Conversions to Act ive/Inactive Forms. Depots.
OP Examples DEF & IFP EPN & DFP Mixer/Loaders Homeowners Parathion DEF Others
Actions Restrict Use Reentry Times Revise Instructions Protective Clothing
Monitor Oxons, C y c l i c s Detoxification Damage i n Blood
Target Cells Molecules
Muscle Nerve Serum, Tissue Levels. Kinetics AChE ΝΤΕ Acute Effects
Gene Regulation
Long-Term Damage Protein, Nucleic Acid Syntheses
Identify Toxicities
Animal, Tissue Molecule Screens
Neuropathy Myopathy MEΡ Damage Cholinergic or Neuropathic
Give Antidotes Prevent Aging
Stimulate Reinnervation Therapy Revise Registration Procedures
In Dermal Exposure Related to Pesticide Use; Honeycutt, R., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1985.
D E R M A L E X P O S U R E R E L A T E D TO PESTICIDE USE
482 W o r k p l a c e and
Environment: I s o f e n p h o s R e s i d u e s on Tomatoes
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IFP I s o f e n p h o s ( I F P ) i s t h e a c t i v e i n g r e d i e n t of t h e r e g i s t e r e d p e s t i c i d e O f t a n o l ; l a s t f a l l i t was a p p l i e d as a g r a n u l a r f o r m u l a t i o n t o s o i l i n a p a r t o f Sacramento County, C a l i f o r n i a , as p a r t o f an e r a d i c a t i o n p r o g r a m a g a i n s t t h e J a p a n e s e B e e t l e . S i n c e t h e i n f e s t e d a r e a i n c l u d e d y a r d s and p r i v a t e d w e l l i n g s , t h e r e was some c o n c e r n over exposures o f p e r s o n s t o r e s i d u e s i n s o i l , water and a i r , and, p o t e n t i a l l y , from f r u i t s and v e g e t a b l e s g r o w n i n t h e y a r d s n e a r b y . To e v a l u a t e t h e l a t t e r p o s s i b i l i t y , t o m a t o e s were a n a l y z e d f r o m s o i l f r o m an e x p e r i m e n t a l plot t r e a t e d w i t h O f t a n o l a t t h e r a t e , and 5 t i m e s t h e r a t e u s e d i n the e r a d i c a t i o n program. IFP was both r e l a t i v e l y p e r s i s t e n t i n s o i l and c o n v e r t e d i n t o i t s oxon ( T a b l e I I I ) . However, no d e t l e c t a b l e r e s i d u e s were found i n whole t o m a t o e s , and o n l y t r a c e s o f r e s i d u e were p r e s e n t i n s u r f a c e r i n s e s o f tomatoes even when t r e a t m e n t s were 5 t i m e s the n o r m a l r a t e .
Table
III.
IFP
Residue
i n S o i l s and
Tomatoes T r e a t e d
on
8/28/83 Sample
Soil ppm
Tomato Surface Pg/cm2
Treatment lb/acre *
2 10 10 2 10 2 10
Sampling Date 9/4/83 9/4/83 10/28/83 9/4/83 9/4/83 10/28/83 10/28/83
IFP Oxon
IFP
1.90 14.0 10.8
0.35 1.0 3.8
0.047 0.012 0.23 0.19
