Risk Benefit Analysis: Role in Regulation of Pesticide Registration

Jul 23, 2009 - However, because of time limitations we will restrict our consideration to adverse health effects in man), (3) principles and problems ...
0 downloads 0 Views 429KB Size
Download PDF
28

Downloaded via YORK UNIV on December 2, 2018 at 17:37:37 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

Risk Benefit Analysis: Role in Regulation of Pesticide Registration ROBERT A. N E A L Center in Toxicology, Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232

The Environmental Protection Agency regulates the use of pesticides in such a way that they are permitted for use when the beneficial effects are deemed to outweigh the risks that may occur to man and his environment on use of those pesticides. Thus, in regulating pesticides, the EPA resorts to benefit and risk analysis as pertains to specific pesticides and specific uses of pesticides. Risk-benefit analysis as related to pesticides will be discussed from the following points of view; (1) how does one determine risk, (2) what are the potential adverse health effects in man from exposure to pesticides, (it must be recognized that adverse effects of pesticides on wildlife and non-target organisms are also an important part of risk-benefit analysis. However, because of time limitations we will restrict our consideration to adverse health effects in man), (3) principles and problems concerning the estimation of risk to man from exposure to pesticides and (4) effects of pesticides that are considered to be beneficial. Determination of P o t e n t i a l Risk There a r e a number of procedures that may be used i n d e t e r mining p o t e n t i a l adverse h e a l t h r i s k i n man from exposure to p e s t i c i d e s . These i n c l u d e epidemiology, which can be a p p l i e d to p e s t i c i d e s c u r r e n t l y i n use i n an attempt to determine i f any adverse h e a l t h e f f e c t s i n man are evident from the r e g i s t e r e d uses of the p e s t i c i d e . Animal bioassays, perhaps the most important methodology used i n determining p o t e n t i a l adverse h e a l t h r i s k to man from exposure to p e s t i c i d e s , can be performed 0097-6156/81/0160-0469$05.00/0 © 1981 American Chemical Society Bandal et al.; The Pesticide Chemist and Modern Toxicology ACS Symposium Series; American Chemical Society: Washington, DC, 1981.

470

THE

PESTICIDE

CHEMIST

A N D

M O D E R N

TOXICOLOGY

on new p e s t i c i d e products which are intended f o r use. The animal bioassays can a l s o be used to assess p o t e n t i a l adverse h e a l t h e f f e c t s of p e s t i c i d e s c u r r e n t l y Γη use f o r which the data base i s considered by EPA to be inadequate. Biochemical or morphological changes which occur i n nonmammalian species or i n b a c t e r i a l or mammalian c e l l s on exposure to p e s t i c i d e s can a l s o be used to assess the p o t e n t i a l adverse h e a l t h e f f e c t s of p e s t i ­ c i d e s . The major current use of these l a t t e r t e s t s i s the d e t e r ­ mination of the mutagenic p r o p e r t i e s of p e s t i c i d e s or contami­ nants of these p e s t i c i d e s . P o t e n t i a l Adverse Health E f f e c t s There are a number of p o t e n t i a l adverse h e a l t h e f f e c t s which may occur i n man on exposure to p e s t i c i d e s . These i n c l u d e acute t o x i c i t y or t o x i c i t y which occurs i n a very s h o r t period of time a f t e r exposure to the p e s t i c i d e , u s u a l l y l e s s than 24 hours; organ and organ system t o x i c i t y , that i s , damage to organ systems such as kidneys or l i v e r ; damage to the nervous system; to the blood forming system (the hematopoetic system); t o x i c i t y to the r e p r o d u c t i v e system of males or females of the s p e c i e s ; teratogenesis or b i r t h d e f e c t s ; immune system t o x i c i t y ; c a r c i n o ­ g e n i c i t y ; and mutations of both somatic and germ c e l l s . In ex­ amining the p o t e n t i a l t o x i c i t y of a p e s t i c i d e intended f o r use or reexamining p e s t i c i d e s c u r r e n t l y i n use these a r e the major t o x i c i t y endpoints which are considered. As noted above these t o x i c i t y endpoints are examined f o r using epidemiology, rodent bioassays and examination f o r biochemical or morphological changes i n nonmammalian s p e c i e s or i n b a c t e r i a l or mammalian c e l l s i n culture. P r i n c i p l e s and Problems i n Risk Assessment A commonly used p r i n c i p l e i n r i s k assessment i s the "no observed e f f e c t l e v e l " which i s defined as the dosage of the compound at which no adverse h e a l t h e f f e c t i s detected e i t h e r i n e p i d e m i o l o g i c a l s t u d i e s i n man or i n rodent b i o a s s a y s . The "no observed e f f e c t l e v e l " may apply to both a v a r i e t y o f t o x i c e f ­ f e c t s or to a s p e c i f i c t o x i c e f f e c t . The "no observed e f f e c t l e v e l " i s an important p r i n c i p l e i n e s t i m a t i n g and c o n t r o l l i n g r i s k to man from exposure to t o x i c chemicals. A second impor­ tant p r i n c i p l e i n r i s k assessment are the s o - c a l l e d s a f e t y f a c t o r s . These f a c t o r s are a p p l i e d to the "no observed e f f e c t l e v e l " f o r a p a r t i c u l a r t o x i c e f f e c t of a chemical to provide an a d d i t i o n a l margin of s a f e t y f o r humans exposed to the chemical. The numerical value of the s a f e t y f a c t o r s range from a p p r o x i ­ mately 10 f o r i n h i b i t i o n of enzymes such as a c e t y l c h o l i n e s t e r a s e to 100 f o r organ system e f f e c t s . Higher s a f e t y f a c t o r s are sometimes a p p l i e d f o r t o x i c e f f e c t s on r e p r o d u c t i o n , t e r a t o ­ genesis e t c . Another p r i n c i p l e used i n r i s k assessment i s the

Bandal et al.; The Pesticide Chemist and Modern Toxicology ACS Symposium Series; American Chemical Society: Washington, DC, 1981.

28.

NEAL

Risk Benefit

Analysis

471

"maximum t o l e r a t e d dose". This i s the highest dose which i s administered i n a rodent bioassay. I t i s a dose which causes some t o x i c o l o g i c a l or pharmacological e f f e c t s i n the e x p e r i mental animal. However, these t o x i c o l o g i c a l - p h a r m a c o l o g i c a l e f f e c t s should, i d e a l l y , not i n t e r f e r e w i t h the determination of the a b i l i t y of the compound to cause the t o x i c e f f e c t i n question. The a d m i n i s t r a t i o n of the maximum t o l e r a t e d dose i s a c o n t r o v e r s i a l p r a c t i c e . On the one hand i t i s argued that to determine the p o t e n t i a l f o r the occurrence of a t o x i c e f f e c t i n a l a r g e human p o p u l a t i o n using a s m a l l number of animals, a dose which i s orders of magnitude higher than the expected human exposure must be administered. On the other hand, i t i s argued that the maximum t o l e r a t e d dose overloads normal metabolic pathways and exceeds the c a p a c i t y f o r e x c r e t i o n of a chemical and, t h e r e f o r e , i s not p h y s i o l o g i c a l . Thus, data obtained using the "maximum t o l e r a t e d dose" have l i t t l e o r no v a l i d i t y i n p r e d i c t ing t o x i c e f f e c t s i n man. In s p i t e o f t h i s argument, the "maximum t o l e r a t e d dose" i s s t i l l an e s t a b l i s h e d p a r t of t e s t i n g f o r t o x i c i t y endpoints and w i l l l i k e l y continue to be used u n t i l a d d i t i o n a l data i s brought to bear that i n d i c a t e s that some of the l a r g e r doses being administered i n rodent bioassays a r e i n v a l i d i n p r e d i c t i n g the p o t e n t i a l adverse h e a l t h e f f e c t s i n man from exposure to the p e s t i c i d e . Another area of controversy i n r i s k assessment i s the existence o r l a c k of e x i s t e n c e o f t o x i c i t y thresholds f o r a chemical f o r i r r e v e r s i b l e e f f e c t s such as c a r c i n o g e n i c i t y . I think most t o x i c o l o g i s t s w i l l agree there i s a threshold f o r any b i o l o g i c a l e f f e c t of a chemical, i n c l u d ing c a r c i n o g e n e s i s . In other words there i s a l e v e l of exposure below which normal r e p a i r mechanisms, metabolic mechanisms f o r i n a c t i v a t i o n and b a r r i e r s to p e n e t r a t i o n o f a chemical to a target s i t e which would not allow the compound to exert i t s t o x i c e f f e c t . However, f o r i r r e v e r s i b l e e f f e c t s such as cancer, the e x i s t e n c e of such a threshold i s d i f f i c u l t to demonstrate experimentally. Therefore, the d i s c u s s i o n i s l i k e l y to continue u n t i l experimental data demonstrating the e x i s t e n c e of a t h r e s hold i s obtained. In the meantime r e g u l a t o r y agencies w i l l continue to r e g u l a t e on the b a s i s that there i s no threshold f o r i r r e v e r s i b l e e f f e c t s such as c a r c i n o g e n i c i t y and mutagenicity. Another area of c o n s i d e r a b l e u n c e r t a i n t y i s the e s t i m a t i o n of the r i s k to man from exposure to chemicals which have been shown to be mutagenic. I t i s c l e a r that exposure o f man to mutagenic chemicals needs to be c o n t r o l l e d . However, i t i s not c l e a r how one goes about determining the r i s k to man implied by exposure to mutagenic chemicals. Much more work needs to be done i n t o t r y i n g to determine what i s an acceptable l e v e l of exposure to a mutagenic chemical. F i n a l l y , another area of controversy i s the p r a c t i c e of estimating the number of tumors that may occur i n a human p o p u l a t i o n on exposure to a c e r t a i n l e v e l of a chemical as c a l c u l a t e d using data on cancer i n c i d e n c e obtained by exposure of experimental animals to v a r i o u s l e v e l s of the chemical. Some

Bandal et al.; The Pesticide Chemist and Modern Toxicology ACS Symposium Series; American Chemical Society: Washington, DC, 1981.

THE PESTICIDE CHEMIST AND MODERN TOXICOLOGY

472

argue that the inaccuracy o f t h i s q u a n t i t a t i v e r i s k e x t r a p o l a t i o n p r a c t i c e i s so great that i t should not be used. Others, i n c l u d i n g myself, b e l i e v e that q u a n t i t a t i v e r i s k e x t r a p o l a t i o n i s a u s e f u l e x e r c i s e that tends to account f o r the potency of oncogenic chemicals and i s an i n d i s p e n s a b l e t o o l to the r e g u l a tor i n making judgments about chemicals which cause i r r e v e r s i b l e effects. B e n e f i c i a l E f f e c t s of P e s t i c i d e s I think the e f f e c t s of a p e s t i c i d e which a r e g e n e r a l l y considered b e n e f i c i a l are, f o r example, i t s e f f e c t on the cost of a g r i c u l t u r a l products. A new p e s t i c i d e may decrease the cost of production of a food or f i b e r product. Therefore i t should be considered b e n e f i c i a l f o r that reason. Likewise, the e l i m i n a t i o n of the use of an o l d p e s t i c i d e may i n c r e a s e the cost of the food or f i b e r . Use of p e s t i c i d e s may provide increased r e creational opportunities. E l i m i n a t i o n or c o n t r o l of human disease organism would of course be considered a b e n e f i t . L i k e wise, the e l i m i n a t i o n or c o n t r o l of unwanted animals o r p l a n t s would a l s o be considered a b e n e f i c i a l e f f e c t of p e s t i c i d e s . Summary With these various data elements i n hand, the r e g u l a t o r i s i n a p o s i t i o n to make judgments about the d e s i r a b i l i t y of a l l o w i n g continued marketing of a p e s t i c i d a l product that has the p o t e n t i a l to cause adverse h e a l t h e f f e c t i n man. Of most importance i n t h i s d e c i s i o n process i s the t o x i c potency of the chemical, the degree of human exposure and the r e v e r s i b i l i t y ( i . e . organ damage) or i r r e v e r s i b i l i t y ( i . e . cancer, teratogenesis) of the t o x i c e f f e c t . The options a v a i l able to the r e g u l a t o r are a ban on the use of the chemical, r e s t r i c t i o n of some uses and methods of a p p l i c a t i o n of the p e s t i c i d e , or r e l a t i v e l y u n r e s t r i c t e d use. Which of these options i s chosen w i l l depend on the c o n s i d e r a t i o n of the s c i e n t i f i c assessment of the r i s k , the economic c o n s i d e r a t i o n of the b e n e f i t s and, unfortunately too o f t e n , the p o l i t i c a l c l i m a t e a t the time the d e c i s i o n i s made and the p o l i t i c a l persuasion of the person making the d e c i s i o n . Of these various elements, the t o x i c o l o g y data r e l a t i v e to the p o t e n t i a l t o x i c i t y of the compound i n question i s of greater importance. However, the experience and judgment of the person e v a l u a t i n g the data i s as important as the data i t s e l f . Toxicology i s not y e t an exact science; nor i s i t l i k e l y to become one i n the foreseeable f u t u r e . Thus, the a b i l i t y of an experienced and o b j e c t i v e t o x i c o l o g i s t to examine competently derived data and a r r i v e a t an assessment of the p o t e n t i a l r i s k to man from exposure to the chemical i s the key element i n the process of r i s k - b e n e f i t a n a l y s i s . RECEIVED March 18,

1981.

Bandal et al.; The Pesticide Chemist and Modern Toxicology ACS Symposium Series; American Chemical Society: Washington, DC, 1981.