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22 Reproductive and Developmental Toxicity Risk Assessment Jerry M. Smith Rohm and HaasCo.,Independence Mall West, Philadelphia, P A 19105

Risk assessment of reproductive and developmental toxicity requires 1) hazard identification, 2) dose-effect, dose-response evaluation, 3) exposure assessment, and 4) risk characterization. Reproductive hazards may involve either male or female, and range from decreased libido to failure of the mother to properly nurse the infant. Developmental hazards affect the conceptus and range from death to the formation of viable but societally dependent offspring. Subchronic, chronic, multigeneration and teratogenic studies provide the majority of data used for hazard identification and dose-effect, dose-response evaluation. Genetic, pharmacokinetic, metabolism, and specially designed investigative studies provide data on the mode of action, target site, delivered dose, primary versus secondary effects, etc. required for characterization of risk. With good characterization of reproductive and developmental risk and exposure assessments, sound risk assessments can be made. Due to vast improvements in food supply and nutrition, r e p r o d u c t i v e s u c c e s s has improved markedly i n many areas o f t h e world. T h i s has been a c c o m p l i s h e d l a r g e l y t h r o u g h advances i n agricultural p r a c t i c e s and t h e use o f p e s t i c i d e s . However, t h e thalidomide and Minamata tragedies, t h e more r e c e n t dibromoc h l oropropane (DBCP) event, and t h e h y s t e r i a of Love Canal demonstrate t h e p o t e n t i a l , r e a l o r p e r c e i v e d , o f a r e p r o d u c t i v e o r developmental c a l a m i t y t h a t might o c c u r w i t h t h e c o n t a m i n a t i o n o f ground water by a p o t e n t r e p r o d u c t i v e o r developmental pesticide toxicant. Therefore, t h e developed world must be a l e r t to potential r e p r o d u c t i v e and developmental hazards and a s s o c i a t e d r i s k t h a t may accompany t h e use o f p e s t i c i d e s . While the potential f o r a reproductive or developmental c a l a m i t y t h r o u g h c o n t a m i n a t i o n o f underground o r s u r f a c e water i s real, it need not happen and w i l l not happen with prudent p e s t i c i d e use and s u r v e i l l a n c e . We have t h e t o o l s , t h e awareness, 0097-6156/ 86/ 0315-0414S06.00/ 0 © 1986 American Chemical Society

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and the responsibility to assure that it does not happen. Essential f o r c o n t i n u e d a p p r o p r i a t e use o f p e s t i c i d e s i s good sound s c i e n t i f i c r i s k assessment i n c l u d i n g an assessment o f r i s k a s s o c i a t e d w i t h c o n t a m i n a t i o n o f ground w a t e r . Assessment o f r e p r o d u c t i v e and development r i s k s associated w i t h t h e use o f p e s t i c i d e s , whether f o r m i x e r - l o a d e r o r consumer, f o l l o w s t h e same g e n e r a l g u i d e l i n e s used f o r any t o x i c i t y risk assessment. The National Research C o u n c i l (NRC) (1) has r e c e n t l y p u b l i s h e d a monograph on r i s k assessment and management and t h e i r procedure i s recommended f o r r e p r o d u c t i v e and developmental risk assessment w i t h some s l i g h t a d d i t i o n s and m o d i f i c a t i o n s . The NRC document calls for hazard identification, doseresponse assessment, exposure assessment, and risk characterization. In an e f f o r t t o p l a c e d e s c r i p t i v e e x p e r i m e n t a l t o x i c i t y r e s u l t s i n a c l e a r e r p e r s p e c t i v e and p l a c e more emphasis on evaluation, this outline deviates slightly from t h e NRC document and c a l l s f o r hazard e v a l u a t i o n , hazard e x t r a p o l a t i o n , exposure assessment and r i s k c h a r a c t e r i z a t i o n . In a d d i t i o n , a few comments on r i s k a c c e p t a b i l i t y a r e g i v e n . Exposure assessments have been a d e q u a t e l y d i s c u s s e d elsewhere i n t h i s symposium and will be discussed here only as they relate to hazard identification, evaluation, extrapolation and risk characterization. L a b o r a t o r y s t u d i e s p r o v i d e d a t a f o r assessment o f r e p r o d u c t i v e and developmental toxicity, and laboratory and environmental s t u d i e s p r o v i d e d a t a f o r assessment o f p o t e n t i a l e x p o s u r e . These d a t a have demonstrated t h a t f o r some p e s t i c i d e s and p e s t i c i d e c a n d i d a t e s , a p o t e n t i a l may e x i s t f o r e x p o s u r e , and r e p r o d u c t i v e or developmental toxicity. This paper does not present an assessment o f t h e p o t e n t i a l r i s k f o r t h e s e p e s t i c i d e s but examines the e s s e n t i a l s t e p s and c r u c i a l elements o f d a t a n e c e s s a r y f o r a p p r o p r i a t e assessment o f h a z a r d and r i s k . U n f o r t u n a t e l y , the i n f o r m a t i o n and d a t a a v a i l a b l e t o a s s e s s o r s o f hazards and r i s k s a r e not always i d e a l and e v a l u a t i o n s must be made on available data. Even more unfortunately, those r e s p o n s i b l e f o r r i s k assessment r e l y t o o f r e q u e n t l y on secondary and t e r t i a r y d a t a s o u r c e s f o r t h e i r e v a l u a t i o n s . T h i s may l e a d t o misinterpretation and over interpretations of original observations. Finally, it must be remembered that when p e s t i c i d e s are p r o p e r l y e v a l u a t e d and u s e d , t h e b e n e f i t s o f p e s t i c i d e s g r e a t l y outweigh the risks associated with their use. The greater potential for disaster, as is being demonstrated in certain underdeveloped a r e a s o f t h e w o r l d , i s f a m i n e . Definitions

and

Terminology

The EPA (2) has r e c e n t l y produced a good d r a f t document assessment o f developmental t o x i c a n t s and t o be c o n s i s t e n t same o r e q u i v a l e n t d e f i n i t i o n s and t e r m i n o l o g y a r e u s e d . Reproductive t o x i c i t y . Adverse e f f e c t s i n t e r f e r e with c o p u l a t i o n , c o n c e p t i o n , maturation of the conceptus.

for the

on e i t h e r parent t h a t may g e s t a t i o n , p a r t u r i t i o n or

416

E V A L U A T I O N O F P E S T I C I D E S IN G R O U N D W A T E R

Developmental toxicity. organism o c c u r r i n g from sexual m a t u r a t i o n .

the

Adverse effects on time o f c o n c e p t i o n

the developing to the time o f

Embryotoxicity and fetotoxicity. Any toxic effect on the c o n c e p t u s as a r e s u l t o f p r e n a t a l e x p o s u r e ; t h e d i s t i n g u i s h i n g f e a t u r e between the terms i s t h e p e r i o d d u r i n g which the i n s u l t occurred. A l t e r e d growth. A significant organ o r body w e i g h t .

alteration

in

fetal

or

neonatal

Functional teratology. Alterations or delays in functional competence o f t h e organism o r organ system f o l l o w i n g exposure t o an agent d u r i n g c r i t i c a l p e r i o d s o f development e i t h e r p r e - o r postnatally. Mai f o r m a t i o n s . A permanent s t r u c t u r a l d e v i a t i o n which i s i n c o m p a t i b l e w i t h o r s e v e r e l y d e t r i m e n t a l t o normal s u r v i v a l or d e v e l o p m e n t .

generally postnatal

Variations. A d i v e r g e n c e beyond t h e usual range o f s t r u c t u r a l c o n s t i t u t i o n which may not have as s e v e r e an e f f e c t on s u r v i v a l o r h e a l t h as a m a l f o r m a t i o n . Hazard

Identification

General toxic hazards, reproductive h a z a r d s , and developmental hazards must be i d e n t i f i e d and c o n s i d e r e d s e p a r a t e l y , y e t t h e i n t e r r e l a t i o n s h i p s between them must be c l e a r l y u n d e r s t o o d . This i s p a r t i c u l a r l y d i f f i c u l t when examining t h e e f f e c t s o f p e s t i c i d e s upon the female s i n c e g e n e r a l t o x i c e f f e c t s may i n d i r e c t l y a f f e c t t h e a b i l i t y o f t h e female t o c o n c e i v e , c a r r y t h e c o n c e p t u s , o r c a r e f o r her o f f s p r i n g . To i d e n t i f y t h e p o t e n t i a l o f p e s t i c i d e s f o r r e p r o d u c t i v e o r developmental h a z a r d s , t h e t o x i c o l o g i s t and regulatory agencies rely primarily on multigeneration and teratogenic studies which normally are adequate. Different p r o t o c o l s and t h e i r s t r e n g t h s , weaknesses, l i m i t a t i o n s , e t c . have been s u b j e c t o f numerous p u b l i c a t i o n s (3) (4) (5) and as such a r e not reviewed h e r e . B a s i c a l l y , m u l t i g e n e r a t i o n s t u d i e s examine the e f f e c t s o f exposure o f both males and females t o p e s t i c i d e s from b e f o r e mating t h r o u g h weaning over at l e a s t two g e n e r a t i o n s and teratogenic studies examine the effects of exposure of the pregnant animal and i t s c o n c e p t u s e s t o the p e s t i c i d e s d u r i n g the p e r i o d o f major development o f t h e c o n c e p t u s . R e p r o d u c t i v e Hazards ( E f f e c t s ) . M u l t i g e n e r a t i o n s t u d i e s not o n l y d e t e c t r e p r o d u c t i v e h a z a r d s , but i n many i n c i d e n c e s t h e y p r o v i d e d a t a f o r i d e n t i f i c a t i o n o f t h e r e p r o d u c t i v e segment t h a t f a i l e d . R e p r o d u c t i v e f a i l u r e o r r e p r o d u c t i v e hazards can be c l a s s i f i e d as impaired mating, impaired c o n c e p t i o n , impaired g e s t a t i o n , impaired parturition or impaired nursing and c a r e f o r t h e neonate o r young. Impaired mating or c o n c e p t i o n can be the r e s u l t o f adverse effects upon t h e m a l e , female, or both. Impaired g e s t a t i o n , p a r t u r i t i o n , n u r s i n g and p e r i / p o s t n a t a l c a r e are the r e s u l t s o f

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a d v e r s e e f f e c t s upon the f e m a l e . (Note: Some adverse e f f e c t s on t h e c o n c e p t u s o r o f f s p r i n g may a d v e r s e l y a f f e c t g e s t a t i o n , n u r s i n g or peri/post natal care.) The e f f e c t s may be d i r e c t o r i n d i r e c t . Developmental Hazards ( E f f e c t s ) . Over t h e l a s t few y e a r s our knowledge and concerns f o r developmental hazards have i n c r e a s e d . We are no l o n g e r concerned only with classical teratogenic e f f e c t s , i . e . s t r u c t u r a l anomalies induced d u r i n g o r g a n o g e n e s i s , but we a l s o r e c o g n i z e t h e p o t e n t i a l f o r e m b r y o / f e t a l t o x i c i t y and functional teratogenicity. C o n s e q u e n t l y , t h e t o x i c o l o g i s t now considers structural teratogenic hazards as a subset of developmental hazards. T h e r e f o r e , not o n l y a r e "teratogenic" s t u d i e s r e q u i r e d t o i d e n t i f y developmental h a z a r d s , but s t u d i e s are required where conceptuses are exposed during major organogenesis and t h e development o f t h e organism i s followed through sexual maturity. Multigeneration studies fulfill the requirement. Developmental hazards may be e x p r e s s e d as death o f c o n c e p t u s , live malformed offspring, developmentally delayed/runted o f f s p r i n g , and f u n c t i o n a l l y i m p a i r e d o f f s p r i n g . Death and a l t e r e d development may be t h e r e s u l t s o f a poor environment p r e s e n t e d by t h e dam or a d i r e c t e f f e c t upon o r g a n o g e n e s i s and development o f the c o n c e p t u s / o f f s p r i n g . P a r e n t a l Hazards ( E f f e c t s ) . For assessment o f r e p r o d u c t i v e and developmental r i s k , p a r e n t a l h a z a r d s , both p a t e r n a l and maternal , must be i d e n t i f i e d and e v a l u a t e d . Parental hazards can be e x p r e s s e d as a l t e r e d n u t r i t i o n a l s t a t e , f u n c t i o n a l i m p a i r m e n t , and s y s t e m i c t o x i c i t y . Because o f p o s s i b l e i n d i r e c t a f f e c t s , knowledge and evaluation of non-reproductive/non-developmental toxicity s t u d i e s are u s e f u l . T h i s i n f o r m a t i o n i s a v a i l a b l e by e x a m i n a t i o n o f s u b c h r o n i c and c h r o n i c t o x i c i t y s t u d i e s . Hazard

Evaluation

Hazard e v a l u a t i o n i s used here t o mean e x a m i n a t i o n and e v a l u a t i o n o f t h e hazards ( a d v e r s e e f f e c t s ) observed i n t o x i c i t y studies, i n c l u d i n g r e p r o d u c t i v e , t e r a t o g e n i c , and general t o x i c i t y s t u d i e s plus other pertinent d a t a . Because o f t h e c o m p l e x i t i e s o f t h e r e p r o d u c t i v e system as w e l l as embryogenesis and m a t u r a t i o n o f t h e conceptus, hazard evaluations must go beyond the mere d e t e r m i n a t i o n o f s t a t i s t i c a l e f f e c t s , no observed e f f e c t levels (NOELS), relationships between dose and response, dose and effects, and t h e d e t e r m i n a t i o n o f margins of safety. Most importantly, for assessment of risk of reproductive and development toxicity the assessor must determine if the reproductive system of the parents or development of the conceptus/offspring are uniquely sensitive to the pesticide. While i t is p o s s i b l e t o d e t e r m i n e a number o f v a r i a b l e s for examination, the c o m p l e x i t i e s o f the i n t e r a c t i o n s o f reproduction preclude a practical set of an all inclusive list for examination. T h e r e f o r e , h a z a r d e v a l u a t i o n s can be guided most effectively by a s k i n g a s e r i e s of questions of the observed results and professionally comparing the answers to known biological facts, data, theories, etc. Some o f t h e most i m p o r t a n t

418


q u e s t i o n s a r e l i s t e d below. Not a l l q u e s t i o n s w i l l have answers, however, t h e e x p e r i e n c e d t r a i n e d i n v e s t i g a t o r s h o u l d be a b l e t o provide appropriate assessment o f t h e d a t a and statements of s i g n i f i c a n c e ( t o x i c o l o g i c a l , b i o l o g i c a l or s t a t i s t i c a l ) . Effect(s). What were t h e t y p e s o f e f f e c t s observed? Did t h e y i n v o l v e a p a r e n t , both p a r e n t s , o r t h e c o n c e p t u s / o f f s p r i n g ? Were they reproductive or developmental? What system(s) were involved? Were t h e e f f e c t s t h e r e s u l t s o f d i r e c t or indirect toxicity? Species. What s p e c i e s were a f f e c t e d ? Were a l l s p e c i e s a f f e c t e d i n t h e same way? Were a l l s p e c i e s a f f e c t e d t o t h e same degree? Dose-effeet/Dose-response. What were t h e d o s e - e f f e c t and d o s e r e s p o n s e r e l a t i o n s h i p s ? (Note: D o s e - e f f e c t s means t h a t t h e t y p e o f e f f e c t w i l l d i f f e r w i t h d i f f e r e n t d o s e s ; d o s e - r e s p o n s e means t h a t t h e degree o f r e s p o n s e o r number r e s p o n d i n g w i l l d i f f e r with different doses.) With increasing doses, were the observed effects biologically (toxicologically) different, similar, r e l a t e d , o r an e x t e n s i o n o n l y i n d e g r e e . How s h o u l d l e s i o n s be t a b u l a t e d t o e x p r e s s i n c r e a s e d e f f e c t s w i t h i n c r e a s e d doses? Does t h e development o f a p a r t i c u l a r l e s i o n p r e c l u d e the development o f a different lesion. For example, a heart malformation is d i f f e r e n t from a m a l f o r m a t i o n o f t h e b r a i n , an anomaly o f t h e long bones o f t h e f o r e l i m b may be s i m i l a r t o an anomaly o f t h e h i n d limb, a severe malformation of the CNS may r e s u l t in death p r e c l u d i n g o b s e r v a t i o n o f a l e s s e r s e v e r e CNS l e s i o n , e t c . What were the no observed e f f e c t l e v e l s ; t h e minimal e f f e c t levels? What were t h e s l o p e s and c h a r a c t e r i s i t i c s o f t h e dose r e s p o n s e curves? Route(s) o f E x p o s u r e . What r o u t e ( s ) o f exposure were used? What were t h e d u r a t i o n and c h a r a c t e r i s t i c s o f t h e exposure? Were t h e r o u t e and d u r a t i o n o f t h e exposure a p p r o p r i a t e f o r e v a l u a t i o n o f t h e expected exposure o f humans? E x p e r i m e n t a l D e s i g n ( s ) . What a r e the weaknesses and s t r e n g t h s o f the experimental designs? What i s t h e u n i t o f a n a l y s i s ? (The individual conceptus o r o f f s p r i n g , o r the l i t t e r . ) Should the results be weighted for statistical analysis? What are t h e appropriate, inappropriate methods of analysis? Should each experiment be g i v e n t h e same weight o f e v i d e n c e ? Relative Sensitivity. What are the relationships between, p a r e n t a l and maternal t o x i c i t y , and r e p r o d u c t i v e e f f e c t s ? What a r e t h e r e l a t i o n s h i p s between maternal t o x i c i t y and developmental toxicity? Was t h e r e p r o d u c t i v e system u n i q u e l y s e n s i t i v e t o t h e pesticide? Was t h e d e v e l o p i n g organism u n i q u e l y s e n s i t i v e t o the pesticide? Hazard

Extrapolation.

Hazard e x t r a p o l a t i o n i s used here t o mean e x t r a p o l a t i o n both from t h e observed e f f e c t l e v e l s t o n o n - t e s t e d l e v e l s w i t h i n t h e t e s t e d

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s p e c i e s and from t e s t e d s p e c i e s t o n o n - t e s t e d s p e c i e s . Hazard e x t r a p o l a t i o n beyond t h e observed s h o u l d be attempted o n l y a f t e r hazard i d e n t i f i c a t i o n , and a f u l l and complete e v a l u a t i o n o f a l l relevant available toxicity data has been completed. The reproductive/developmental t o x i c o l o g i s t must be v e r y s p e c i f i c i n s t a t i n g h i s / h e r c e r t a i n t i e s and u n c e r t a i n t i e s about e x t r a p o l a t i o n beyond the o b s e r v e d . A g a i n , a s e r i e s o f q u e s t i o n s can g r e a t l y a i d t h e r e g u l a t o r and t h e i n v e s t i g a t o r i n a r r i v i n g a t judgements o f the s i g n i f i c a n c e o f the observed data f o r e x t r a p o l a t i o n to the unobserved. L i s t e d below i s a s e r i e s o f q u e s t i o n s h e l p f u l t o t h e regulator and the investigator for extrapolation beyond the observed. Test M o d e l ( s ) . What was t h e a p p r o p r i a t e n e s s o f t h e t e s t model(s) used f o r r e p r o d u c t i v e and developmental hazards a s s o c i a t e d w i t h p e s t i c i d e c o n t a m i n a t i o n o f underground ( d r i n k i n g ) w a t e r . Common sense t e l l s us t h a t e x t r a p o l a t i o n o f r e s u l t s from a s u b c h r o n i c o r chronic drinking water study is more appropriate than extrapolation from some fraction of the LD50 dose given i n t r a p e r i t o n e a l ^ f o r 5 d a y s . L i k e w i s e , c h r o n i c f e e d i n g i s more a p p r o p r i a t e than gavage d o s i n g which i s more a p p r o p r i a t e than dermal e x p o s u r e , e t c . The same c o n c e p t s a p p l y t o r e p r o d u c t i v e and developmental hazard a s s e s s m e n t s . Delivered Dose. What was t h e dose d e l i v e r e d t o the target tissue(s)? V a r i a t i o n s and d i f f e r e n c e s between s p e c i e s , i n d i v i d u a l a n i m a l s and even u n i t s w i t h i n an animal are common when one compares response observed t o v a r i o u s exposure r e g i m e n s . However, examination of delivered dose o f toxicant to target tissues f r e q u e n t l y reduces t h e v a r i a t i o n s and d i f f e r e n c e s . Kimmel and Young (8) have r e c e n t l y p u b l i s h e d a paper d e m o n s t r a t i n g improved p r e d i c t i o n o f t e r a t o g e n i c outcome o f r a t s t o sodium s a l i c y l a t e when blood l e v e l s were u s e d . The more complete the knowledge and u n d e r s t a n d i n g o f t h e a b s o r p t i o n , d i s t r i b u t i o n , m e t a b o l i s m , and e x c r e t i o n w i t h i n the s t u d i e d s p e c i e s and the s p e c i e s o f c o n c e r n , t h e g r e a t e r t h e c o n f i d e n c e t h e i n v e s t i g a t o r has i n e x t r a p o l a t i n g d a t a from one s p e c i e s t o another o r from an observed dose w i t h i n a s p e c i e s t o a n o n - t e s t e d dose i n t h e same s p e c i e s . Structural Activity Relationships. Are t h e r e any structural activity relationships (SAR) between the pesticide under c o n s i d e r a t i o n and p e s t i c i d e s t h a t have a h i s t o r y o f s a f e uses? Structural a c t i v i t y r e l a t i o n s h i p s must be u s e d , not misused o r abused. To be used p r o p e r l y , SAR e v a l u a t i o n s must t a k e into consideration not only chemical structure class and toxic c a t e g o r i e s , but s u b t l e chemical s t r u c t u r a l d i f f e r e n c e s as w e l l as all known b i o l o g i c a l activity and metabolism o f t h e chemical structure c l a s s . Mathematical Model s . There are no biological appropriate mathematical models for evaluation of reproductive or developmental hazards. The best that can be done is to mathematically characterize the dose-response curve in the o b s e r v a b l e range and e s t i m a t e the t h r e s h o l d l e v e l s . The EPA (2) has r e j e c t e d t h e use o f mathematical modeling f o r estimating developmental t o x i c i t y r e s p o n s e s below t h e a p p l i e d dose r a n g e .

420


Statistics. What are t h e s t a t i s t i c a l l i m i t s o f t h e e x p e r i m e n t a l d e s i g n s and what a r e t h e l i m i t s t o the s t a t i s t i c s t h a t can be a p p l i e d to r e p r o d u c t i v e studies and e v a l u a t i o n s ? Statistical evaluations of reproductive and developmental studies present numerous problems including from whether the litter or the i n d i v i d u a l conceptus i s t h e e x p e r i m e n t a l u n i t f o r e v a l u a t i o n , t o t h e e f f e c t s o f w e i g h t i n g o f body w e i g h t s due t o l i t t e r s i z e o r 0 and 100% responses w i t h i n a l i t t e r ( G a y l o r (9) and Nelson and Holson ( 1 0 ) ) . While i t i s i m p o r t a n t i n a l l t o x i c o l o g i c a l s t u d i e s to consult a statistician before conducting an experiment, reproductive and developmental studies a r e more demanding for proper statistical consultation both before and after the conducting of a s t u d y ( i e s ) . Uncertainties. In any hazard or r i s k assessment i t i s e x t r e m e l y important that uncertainties be expressed. Frequently the u n c e r t a i n t i e s are expressed only in s t a t i s t i c a l terms. It is i m p o r t a n t t h a t t h e u n c e r t a i n t i e s a l s o be e x p r e s s e d i n b i o l o g i c a l terms. S t a t i s t i c a l modeling or modeling s t a t i s t i c s has become v e r y p o p u l a r i n h e a l t h r i s k a s s e s s m e n t s , p a r t i c u l a r l y f o r "low dose" extrapolations. As previously stated, there are no mathematical models w i t h a b i o l o g i c a l b a s i s f o r r e p r o d u c t i o n o r developmental hazard e v a l u a t i o n . G a y l o r (11) and Crump (12) have p o i n t e d out some o f t h e deficiencies of using no-observed-effect-levels (NOELS's) and minimal e f f e c t l e v e l s (MEL's) i n r i s k management. B a s i c a l l y , they point out that NOEL's and MEL's are as much a f u n c t i o n of e x p e r i m e n t a l dose s e l e c t i o n s as t h e t r u e d o s e - r e s p o n s e n a t u r e o f t h e t e s t animal t o t h e t o x i c a n t s . Both suggest t h a t a s t a t i s t i c a l a c c e p t a b l e mathematical model be a p p l i e d t o the d a t a i n t h e observed range and t h a t a c o n s i s t e n t end p o i n t such as a 0.1 o r 0.01 i . e . t h e 10% o r 1% e f f e c t l e v e l be e s t i m a t e d . Examination o f data from well conducted toxicological studies, including r e p r o d u c t i v e and t e r a t o g e n i c s t u d i e s suggest t h a t an e s t i m a t e d 10% e x t r a r i s k c o r r e s p o n d s well t o minimal observed e f f e c t l e v e l s and an e s t i m a t e d 1% e x t r a r i s k c o r r e s p o n d s w e l l t o a t h r e s h o l d or noobserved-effect level. Also, consistent end points improve comparison between effects, studying and in general aid evaluation. E s t i m a t i o n o f c o n f i d e n t l i m i t s f o r r i s k and doses about such estimated points help define confidences in a p a r t i c u l a r s t u d y , but add l i t t l e t o c e r t a i n t i e s o r u n c e r t a i n t i e s f o r e x t r a p o l a t i o n s t o low doses o r t o o t h e r s p e c i e s . Therefore, most l i k e l y e f f e c t dose e s t i m a t e s s h o u l d be u s e d . Unfortunately, certainties and uncertainties cannot be expressed with mathematical precision and should not be attempted. C o n f i d e n c e s and u n c e r t a i n t i e s must be expressed as expert opinions with statements o f s u p p o r t . E x p e r t s can u s u a l l y agree t h a t above a s t a t e d " h i g h " exposure a g i v e n response is l i k e l y and t h a t below a s t a t e d "low" exposure t h e response is unlikely. However, between t h e "low" and " h i g h " exposures t h e r e i s an a r e a o f u n c e r t a i n t i e s where e x p e r t s w i l l d i s a g r e e about t h e l i k e l i h o o d o f a g i v e n response t o a p a r t i c u l a r e x p o s u r e .

22.

SMITH

Risk

Reproductive

and Developmental

Toxicity Risk

Assessment

421

Characterization

R i s k c h a r a c t e r i z a t i o n i s an e x p e r t , i n t e g r a t e d , summarization o f hazard identification, evaluation, and extrapolation, plus a characterization of the population(s) at risk and likely exposures. It i s t h e c o n c l u s i o n o f t h e s c i e n t i f i c endeavor t o assess r i s k . It must be p r e c i s e , i n c l u s i v e and s t a t e d i n terms that can be understood and used appropriately for societal judgements on the a c c e p t a b i l i t y o f a r i s k . Risk

Acceptability

As a l l m a t e r i a l s a r e t o x i c t o some organisms under some exposure c o n d i t i o n s , t h e r e i s no " s a f e m a t e r i a l " i n t h e p u r e s t s e n s e , t h e r e are only "safe handling" or "acceptable handling" procedures, or risk management techniques. This is particularly true for pesticides. In t h i s s e n s e , s a f e t y f a c t o r s , margin o f s a f e t y , low dose e x t r a p o l a t i o n s , e t c . are not r i s k assessment t o o l s , t h e y a r e r i s k management t o o l s . Thus w h i l e i t has been noted i n scientific experiments and o b s e r v a t i o n s t h a t animal t o animal v a r i a t i o n s a r e seldom g r e a t e r than an o r d e r o f magnitude and s e n s i t i v i t y from one s p e c i e s t o another i s u s u a l l y w i t h i n a f a c t o r o f t e n , t h e 1/100 s a f e t y f a c t o r f o r e s t a b l i s h i n g a c c e p t a b l e d a i l y i n t a k e (ADI) i s not a r i s k assessment d e c i s i o n , i t i s a r i s k managerial d e c i s i o n with s c i e n t i f i c i n p u t . F o r a c o n t r o l l i n g , r e g u l a t o r y , p e r s p e c t i v e I would l i k e t o paraphrase Marshall Johnson ( 1 3 ) . It can be c o n c l u d e d t h a t a pesticide would need to be (regulated) controlled as a r e p r o d u c t i v e o r developmental hazard o n l y i f the reproductive system or the embryo/fetus are uniquely susceptible to the pesticide. Pesticides that are coeffective reproductive or developmental toxins, that is, adversely affecting the reproductive system or t h e d e v e l o p i n g c o n c e p t u s o n l y a t dose l e v e l s t h a t a d v e r s e l y a f f e c t t h e a d u l t , would not n e c e s s a r i l y be c o n t r o l l e d as r e p r o d u c t i v e o r developmental h a z a r d s . Thus o n l y n o n - c o e f f e c t i v e r e p r o d u c t i v e o r developmental t o x i n s , which a r e t h o s e a f f e c t i n g r e p r o d u c t i o n o r t h e d e v e l o p i n g c o n c e p t u s below t h e dose needed t o a d v e r s e l y a f f e c t the a d u l t would r e q u i r e c o n t r o l . Conclusion In c o n c l u s i o n , r e g u l a t o r s must make d e c i s i o n s and i n v e s t i g a t o r s must e x p r e s s o p i n i o n s based on a v a i l a b l e d a t a and cannot wait f o r a second o r t h i r d r e c y c l i n g t h r o u g h t e s t i n g and e v a l u a t i o n s . If hazard i d e n t i f i c a t i o n and p r e l i m i n a r y exposure e s t i m a t e s suggest the potential o f r e p r o d u c t i v e o r developmental hazard and the p o t e n t i a l f o r e x p o s u r e , both must conduct a hazard assessment and hazard e x t r a p o l a t i o n u t i l i z i n g a l l a v a i l a b l e i n f o r m a t i o n and best science. And, i f t h e assessment demonstrates t h a t r e p r o d u c t i o n o r development is uniquely s e n s i t i v e , i e , t h a t t h e p e s t i c i d e may a f f e c t r e p r o d u c t i o n o r t h e d e v e l o p i n g c o n c e p t u s below t h e dose needed t o a d v e r s e l y a f f e c t t h e a d u l t , then w i t h t h e best e s t i m a t e o f e x p o s u r e , t h e y must perform a r i s k a s s e s s m e n t . The risk assessment must be a s c i e n t i f i c endeavor w h i l e the d e c i s i o n s on

422


risk acceptability judgement.

and r i s k

management

should

be l e f t

to

societal

Literature Cited 1. 2. 3.

4.

5. 6.

7. 8. 9.

10. 11. 12. 13.

"Risk Assessment in the Federal Government: Managing the Process," National Research Council, National Academy Press, Washington, D.C., 1983. "Proposed Guidelines for the Health Assessment of Suspect Developmental Toxicants," Federal Register 49 CFR, November 23, 1984, pp 46325-46331. "U.S. Environmental Protection Agency. 1982. Health effects test guidelines, Chapter II. Specific organ/tissue toxicity -teratogenicity." Office of Toxic Substances. Available from: NTIS, Springfield, VA. PB82-232984. Kimmel, C. Α.; Holson, J. F.; Hogue C. J.; Carlo, G. L . ; "Reliability of experimental studies for predicting hazards to human development." NCTR Technical Report for Experiment No. 6015. 1984; NCTR, Jefferson, Arkansas. "Guidelines for reproduction and teratology of drugs." Bureau of Drugs. Food and Drug Administration, 1966. Food and Drug Administration. Advisory Committee on Protocols for Safety Evaluations. "Panel on Reproduction Report on Reproduction Studies in the Safety Evaluation of Food Additives and Pesticide Residues." Toxicol. Appl. Pharmacol. 1970, 16, 264-296. Collins, T. F. X. "Multigeneration Reproduction Studies"; In "Handbook of Teratology"; Wilson, J. G.; Fraser, F. C., Ed., Plenum Press, New York, N.Y., 1978; Chap 7. Kimmel, C. Α.; Young, J. F. Fundam. Appl. Toxicol. 1983, 3, 250-5. Gaylor, D. W. "Methods and Concepts of Biometrics Applied to Teratology"; In "Handbook of Teratology 4 Research Procedures and Data Analysis": Wilson, J. G.; Fraser, F. C., Eds.; Plenum Press, New York, Ν. Y. 1978; Chap. 14. Nelson, C. J.; Holson, J. F. J. Environ. Pathol. Toxicol. 1978, 2, 187-99. Gaylor, D. W. J. Toxicol. Environ. Health. 1983, 11, 329-36. Crump, K. S. Fundam. Appl. Toxicol. 1984, 4, 854-71. 13. Johnson, Ε. M. Ann. Rev. Pharmacol. Toxicol. 1981, 21, 41729. Johnson, Ε. M. Ann. Rev. Pharmacol. Toxicol. 1981, 21, 417-29.

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November 4, 1985

Evaluation of Pesticides in Ground Water - ACS Publications

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