The Pesticide Chemist and Modern Toxicology - ACS Publications

36 Regulatory Aspects: A Summary PHILIP C. K E A R N E Y

Downloaded by NATL UNIV OF SINGAPORE on May 5, 2018 | https://pubs.acs.org Publication Date: August 10, 1981 | doi: 10.1021/bk-1981-0160.ch036

U.S. Department of Agriculture, Building 050 BARC West, Beltsville, MD 20705

The emerging importance of toxicology in pesticide registration policy has not only depended on major scientific achievements in the discipline of toxicology, but also in the growing involvement of various segments of society who are concerned about risk assessment and public health. These societal groups have also had a major impact on the use of toxicolgical data to force regulatory agencies to develop more sophisticated methods of risk/benefit assessment. This session of the symposium examines some of these public forces that comment on pesticide regulations, and then examines regulations in various countries of the world. Industry is concerned how the intent of the authority granted to the Environmental Protection Agency (EPA) by Congress in the 1972 amendments to the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) are being mandated by a growing number of and changes in regulations, rules and guidelines. The whole process of pesticide registration is perceived as becoming infinitely more complex. A major problem in the reregistration process is the large number of compounds involved (l4OO individual pesticides and 33,000 formulated products encompassing some 15 classes of pesticides). Because of the enormity of the regulatory task, reglations have been proposed and adopted over a period of six to eight years; the process is not yet complete. A number of fundamental changes were made: (1)

The n e g l i g i b l e residue concept was abandoned;

(2)

Studies on non-target organisms ( i . e . environmental studies) were required;

(3)

P e s t i c i d e s were to be c l a s s i f i e d r e s t r i c t e d use; and,

(k)

An assessment o f a p p l i c a t o r o r user hazard was required.

f o r general or

This chapter not subject to U.S. copyright. Published 1981 American Chemical Society

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


546

THE

PESTICIDE

C H E M I S T

A N DM O D E R N TOXICOLOGY

As a r e s u l t o f the change i n r e g u l a t i o n s , the use o f a number o f p e s t i c i d e s has been r e s t r i c t e d , and, i n some cases, r e g i s t r a t i o n s have been canceled. The r e g i s t r a t i o n process has become lengthy and much more complicated. Industry proposes some recommendations that could u l t i m a t e l y b e n e f i t p r i v a t e i n d u s t r y and the p u b l i c . These recommendations include the use o f c e r t i f i e d summaries, c l a r i f i c a t i o n o f the o b j e c t i v e s o f the EPA Good Laboratory P r a c t i c e s program, m o d i f i c a t i o n o f the current proposed toxicology g u i d e l i n e s and a c q u i s i t i o n o f a s t a b l e , a u t h o r i t a t i v e body o f s c i e n t i f i c personnel to review t o x i c o l o g y data. The environmental groups, represented by the Environmental Defense Fund (EDF), are concerned about the accuracy o f t o x i cology data being provided to the Environmental P r o t e c t i o n Agency to do the r i s k / b e n e f i t a n a l y s i s . The environmentalists want comprehensive t e s t i n g and assessment o f p e s t i c i d e s before they are widely disseminated i n t o the environment. The reason f o r these concerns are based on some unacceptable l a b o r a t o r y p r a c t i c e s that have been found i n s e v e r a l drug and p e s t i c i d e l a b o r a t o r i e s . They s t r o n g l y support uniform requirements f o r t e s t i n g because o f past i n a c c u r a c i e s and encourage good l a b o r a t o r y p r a c t i c e s . EDF favors a p r e v e n t a t i v e approach to p e s t i c i d e r e g i s t r a t i o n based on suggested evidence from animal studies r a t h e r than a c t u a l harm to human populations. They b e l i e v e the s o c i e t a l c o s t s are too great to r i s k l e s s than near absolute safety i n p e s t i c i d e r e g i s t r a t i o n . To a l e s s e r extent consumer groups have had an impact on t o x i c o l o g y as i t r e l a t e s to p e s t i c i d e s . The Consumer Federation o f America, the nation's l a r g e s t consumer o r g a n i z a t i o n , and other consumer groups have not been h i g h l y a c t i v e i n p e s t i c i d e r e g u l a tory a f f a i r s , but sometimes consumer and environmental i n t e r e s t s work j o i n t l y to comment on Federal r e g u l a t o r y p o l i c i e s . They c l o s e l y s c r u t i n i z e proposed g u i d e l i n e s published i n the F e d e r a l Register. Consumer groups work hard to assess and report the views o f ordinary people, p a r t i c u l a r l y t h e i r pocketbook i n t e r e s t s , and gain c r e d i b i l i t y from t h i s grass roots connection. J o i n t i n d u s t r y , p r o f e s s i o n a l , and consumer seminars and work sessions are being convened i n r e l a t e d f i e l d s (e.g., Food Safety Council) because they agree that Government i s s e r i o u s l y d e f i c i e n t i n i t s handling o f t h e i r i n t e r e s t s . Consumer groups are i n t e r e s t e d i n working with s c i e n t i f i c s o c i e t i e s , l i k e ACS, who want to explore the p o s s i b i l i t y o f frank and open meetings with consumer advocates who have the same long range i n t e r e s t s as i n d u s t r y and science i n safe, e f f e c t i v e , and reasonably p r i c e d pesticides. Before d i s c u s s i n g r e g u l a t i o n o f p e s t i c i d e s , some d i s c u s s i o n of the use o f animal data i n a s s e s s i n g human r i s k i s necessary, since i t forms the b a s i s o f many judgments from both s o c i e t a l and r e g u l a t o r y groups. There are three fundamental methods o f e s t i mating p o t e n t i a l human r i s k as a r e s u l t o f exposure to t o x i c substances. These are ( l ) e p i d e m i o l o g i c a l s t u d i e s , (2) animal



36.

KEARNEY

Regulatory

Aspects: A

Summary

547

t e s t s , and (3) short-term or i n v i t r o analyses such as studies o f DNA damage or mutagenesis. Of these the g r e a t e s t confidence i s placed upon e p i d e m i o l o g i c a l studies i n humans. Due to problems i n o b t a i n i n g human e p i d e m i o l o g i c a l data, we are l e f t then with the next a l t e r n a t i v e — the use of other mammalian species as human surrogates. The r a t i o n a l e f o r using animals i n t o x i c o l o g i c a l t e s t i n g are based on the f a c t that mammals are anatomically, p h y s i o l o g i c a l l y and b i o c h e m i c a l l y s i m i l a r , have s i m i l a r h e a l t h and disease manifestations and causes, and respond s i m i l a r l y to exogenous chemical, b i o l o g i c a l , and p h y s i c a l agents. The v a l i d i t y of animal data i n assessing human r i s k must consider f a c t o r s such as t e s t animal s p e c i e s , route o f a d m i n i s t r a t i o n , dose l e v e l s , adequacy and u n i f o r m i t y of p a t h o l o g i c a l examinat i o n s , disease prevalence i n c o n t r o l animals, and f a l s e negatives or f a l s e p o s i t i v e s t a t i s t i c a l analyses. The f i v e most important b i o l o g i c a l parameters which best detemine the potency or v i r u lence of an animal carcinogen are number o f species a f f e c t e d , number o f t i s s u e s i t e s a f f e c t e d , l a t e n c y p e r i o d s , dose-response r e l a t i o n s h i p s , and nature or s e v e r i t y o f l e s i o n s induced. A l l of these f a c t o r s , plus others, must be considered i n e x t r a p o l a t i n g animal to human r i s k s i t u a t i o n s . In the United S t a t e s , the Environmental P r o t e c t i o n Agency (EPA) i s r e s p o n s i b l e f o r p e s t i c i d e r e g u l a t i o n , and more s p e c i f i c a l l y f o r a s s e s s i n g the degree o f r i s k posed by the numerous p e s t i c i d e s a v a i l a b l e , and determining what l e v e l of r i s k , tempered by b e n e f i t , s o c i e t y ought to accept. Risk/benefit analysis i s the c h i e f t o o l e s t a b l i s h e d i n the b a s i c p e s t i c i d e law, the F e d e r a l I n s e c t i c i d e , Fungicide and Rodenticide Act (FIFRA) f o r reaching r e g u l a t o r y d e c i s i o n s . The Rebuttable Presumption Against R e g i s t r a t i o n (RPAR) process i s the review mechanism by which r i s k s and b e n e f i t s are measured. Animal s t u d i e s form the primary b a s i s f o r assessing p e s t i c i d e r i s k . To a l i m i t e d extent, human e p i d e m i o l o g i c a l data are used to judge r i s k , although prudent p u b l i c a d m i n i s t r a t i o n cannot wait to act u n t i l an e f f e c t i s observed i n a human population. EPA i s concerned, however, that e x t r a p o l a t i o n from animal data to human r i s k i s , while s c i e n t i f i c a l l y supported, s t i l l f u l l of u n c e r t a i n t y . One of the most troublesome areas i s e x t r a p o l a t i n g cancer data i n animals to a r r i v e at r i s k assessment i n humans. R e l i a b l e short-term b i o assays or appropriate b a t t e r i e s of short-term t e s t s o f f e r one o f the best and perhaps most expedient methods f o r conducting r i s k assessments on a c t i v e i n g r e d i e n t s , and p o s s i b l y i n e r t s and contaminants i n the f u t u r e . Improved human exposure models w i l l a l s o play a major r o l e i n future p e s t i c i d e p o l i c y d e c i s i o n s . A t y p i c a l example of r i s k / b e n e f i t analyses by EPA was the recent RPAR against the h e r b i c i d e pronamide. Pronamide was found to produce l i v e r tumors i n male mice. A f t e r c a r e f u l e v a l u a t i o n of the exposure l e v e l s i n humans, the number o f excess tumors to be expected from t h i s exposure, the monetary l o s s i f the r e g i s t r a t i o n of pronamide were canceled, and the a v a i l a b i l i t y of

American Chemical Society Library 1155 16th St., N.W. Bandal et al.; The Pesticide Chemist and Modern Toxicology Washington, D.C. Society: 20036Washington, DC, 1981. ACS Symposium Series; American Chemical


548

THE

PESTICIDE

CHEMIST

A N D

M O D E R N

TOXICOLOGY

s u b s t i t u t e h e r b i c i d e s , EPA proposed that the r e g i s t r a t i o n o f pronamide should be continued a f t e r some changes i n use p a t t e r n and method of a p p l i c a t i o n . P e s t i c i d e r e g i s t r a t i o n requirements i n Europe today do not d i f f e r b a s i c a l l y from those i n the United States or elsewhere on an i n t e r n a t i o n a l b a s i s . The key a d m i n i s t r a t i v e processing of p e s t i c i d e r e g i s t r a t i o n l i e s with the M i n i s t r i e s o f A g r i c u l t u r e as compared to EPA i n the U.S. A d m i n i s t r a t i o n o f the European requirements may be somewhat more f l e x i b l e . For example, a checkl i s t developed by various c o u n t r i e s may be used to provide f u l l or p r o v i s i o n a l r e g i s t r a t i o n s without c a r c i n o g e n i c i t y or chronic t o x i c o l o g y data, when a l l a v a i l a b l e data, i n c l u d i n g mutagenicity and residue t e s t s , are favorable. Harmonization of r e g i s t r a t i o n standards i s achieved by the Council of Europe through p u b l i c a t i o n of P e s t i c i d e s . From a t o x i c o l o g y standpoint, a few c o u n t r i e s i n Europe have issued d e t a i l e d t e s t i n g g u i d e l i n e s i n the f i e l d of t o x i c o l o g y . I t i s a n t i c i p a t e d that some c o u n t r i e s may soon adopt s i m i l a r , more s t r i n g e n t t o x i c o l o g y t e s t i n g r e q u i r e ments. One trend that i s apparent i n Europe i s a tendency to r e q u i r e more e c o l o g i c a l t e s t i n g . One d i f f e r e n c e e x i s t i n g between European c o u n t r i e s deals with s e t t i n g tolerances f o r p e s t i c i d e residues i n crops. Canadian p e s t i c i d e a u t h o r i t y r e s i d e s i n two Acts of Parliament: the P e s t i c i d e C o n t r o l Products Act administered by A g r i c u l t u r e Canada, and the Food and Drugs Act administered by Health and Welfare Canada. A g r i c u l t u r e Canada i s r e s p o n s i b l e f o r r e g i s t r a t i o n of a l l p e s t i c i d e s s o l d i n Canada. I t obtains expert advice from a number of other governmental agencies. Health and Welfare Canada promulgates r e g u l a t i o n s on the maximum residue l i m i t s of p e s t i c i d e s p e r m i s s i b l e on food at the time i t f i r s t enters commerce. The major t o x i c o l o g i c a l e v a l u a t i o n of p e s t i c i d e s can be subdivided i n t o two major areas: ( l ) data p e r t a i n ing to safety of food r e s i d u e s , and (2) data p e r t a i n i n g to occupational exposure and bystander exposure. T h e o r e t i c a l d a i l y intake (TDI) values and n e g l i g i b l e d a i l y intake (NDI) values are used to estimate exposure and set r e g i s t r a t i o n p o l i c y . Although no s p e c i f i c l e g a l requirements e x i s t f o r studies which must be submitted to support s a f e t y i n use o f p e s t i c i d e s , c e r t a i n u n o f f i c i a l minimum requests must be met i n Canada. These i n c l u d e acute o r a l and dermal LD^Q'S; acute i n h a l a t i o n LD^o's; eye and skin i r r i t a t i o n s t u d i e s ; feeding s t u d i e s o f at l e a s t 90 days duration on adequate numbers of animals o f at l e a s t two species, one o f which would be a non-rodent s p e c i e s ; absorption, d i s t r i b u t i o n and e x c r e t i o n data in one of the species used i n the 90 day s t u d i e s ; mutagenicity screening s t u d i e s , and any s p e c i a l studies i n d i c a t e d by the chemical s t r u c t u r e of the compound under t e s t . P e s t i c i d e r e g u l a t i o n s i n the People's Republic of China began to take form in the l a s t f i v e years. A s e r i e s of n a t i o n a l conferences held i n 1976 and 1978 produced two papers e n t i t l e d "Proposed Regulations of Experimental Methods f o r P e s t i c i d e


36.

KEARNEY

Regulatory

Aspects:

A

Summary

549


T o x i c o l o g y " and "Proposed Regulations f o r P e s t i c i d e Toxicology and Residues" that form the b a s i s o f the r e g u l a t o r y program. An a p p l i c a t i o n f o r a new p e s t i c i d e progresses through a review system i n v o l v i n g an I n s t i t u t e f o r C o n t r o l l i n g P e s t i c i d e s , followed by simultaneous review by the M i n i s t r y o f Chemical Engineering, M i n i s t r y o f Public Health, and the Environmental P r o t e c t i o n Agency. Formal r e g i s t r a t i o n i s granted by the Ministry of Agriculture. As an example, a new f u n g i c i d e (DKS) i s traced through i t s t e s t i n g and review a t various stages o f development. This promising f u n g i c i d e was o f f i c i a l l y banned when a l a r g e scale study suggested s t a t i s t i c a l evidence f o r h e a l t h effects. RECEIVED March 10, 1981.


The Pesticide Chemist and Modern Toxicology - ACS Publications

Recommend Documents