Conceptual Basis for Risk Assessment - ACS Symposium Series (ACS

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1 Conceptual Basis for Risk Assessment

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JOSEPH V. RODRICKS Environ Corporation, Washington, DC 20006 ROBERT G. TARDIFF Board on Toxicology and Environmental Health Hazards, National Academy of Sciences/ National Research Council, Washington, DC 20037

Risk is the probability of injury or death. For some activities we encounter no great difficulties in determining risk. Thus, it is possible to estimate quite accurately the risks of accidental death due to such activities as driving a car, working in a coal mine, riding a bicycle, hiking in the desert, or eating low-acid canned foods (botulism). Estimation of such risks is readily accomplished because historical statistical data are available, and because there is l i t t l e difficulty in demonstrating the causal connections between injury and these types of activities. To estimate such risks is the work of actuaries, most of whom are employed by insurance companies. Other risks cannot be so easily estimated because the necessary actuarial data do not exist and frequently cannot even be collected. Many of the potential risks from exposure to chemicals are in this second category. In addition to the absence of actuarial data relating to them, these risks tend to have the following characteristics: (i) Suspicion that exposure may lead to injury usually results from experimental observations, commonly involving animals, (ii) Identifiable injury does not occur immediately following exposure, and may sometimes not occur for many years after initial exposure.

0097-6156/ 84/ 0239-0003S06.00/ 0 © 1984 American Chemical Society

Rodricks and Tardiff; Assessment and Management of Chemical Risks ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

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ASSESSMENT A N D M A N A G E M E N T O F C H E M I C A L RISKS

( i i i ) The c o n d i t i o n s o f exposure (level, frequency, d u r a t i o n , route) that g i v e r i s e t o experimentally-observed i n j u r y are f r e q u e n t l y d i f f e r e n t (sometimes r a d i c a l l y so) from the c o n d i t i o n s o f a c t u a l human exposure, which themselves may not be w e l l - d e f i n e d , (iv) The experimental environments i n which informat i o n i s c o l l e c t e d on p o t e n t i a l i n j u r y from a chemical exposure are u s u a l l y f r e e o f the large number o f f a c t o r s i n the human environment that may b i o l o g i c a l l y or chemically i n t e r a c t with the chemical, and thus a l t e r i t s c a p a c i t y t o cause injury. (v) Experiments used t o c o l l e c t data on chemical i n j u r y may involve s e v e r a l d i f f e r e n t s p e c i e s of t e s t animals, and they may y i e l d q u a n t i t a t i v e l y , and sometimes q u a l i t a t i v e l y , d i f f e r e n t results. It i s u s u a l l y not f e a s i b l e t o i d e n t i f y the species that best mimics human response, assuming there i s one a t a l l . (vi) E p i d e m i o l o g i c a l i n v e s t i g a t i o n s o f c h r o n i c exposure or i n j u r y , while y i e l d i n g data on the species o f concern, are f r e q u e n t l y limited because they can not u s u a l l y d e t e c t s m a l l but possibly important effects; because they frequently can not provide evidence o f s t r i c t causation; and because they usually do not provide quantitative dose-response data. Moreover, they can be conducted only after exposure has occurred and thus can not be used t o decide whether exposure t o a newly-introduced substance should be permitted. Given the above, i t would seem f o o l i s h t o attempt t o p r e d i c t the human r i s k s a s s o c i a t e d with exposures t o chemicals. Many s c i e n t i s t s faced with such a problem are not w i l l i n g t o attempt an answer, and proclaim the need f o r more research. They b e l i e v e that i t would be s c i e n t i f i c a l l y imprudent ever t o go beyond the e m p i r i c a l data t o p r e d i c t r i s k s under d i f f e r e n t conditions. T h i s b e l i e f ignores the p o s s i b i l i t y that low but nonetheless important r i s k s e x i s t under c o n d i t i o n s o f exposure that defy our attempts a t d i r e c t o b s e r v a t i o n . In a d d i t i o n , i n the context o f c u r r e n t law, such a view a u t o m a t i c a l l y t r a n s l a t e s t o a r e g u l a t o r y d e c i s i o n t o permit exposures t o continue or t o begin, because there would be no reason t o l i m i t exposures a t any l e v e l below those f o r which e m p i r i c a l information on h e a l t h e f f e c t s i s a v a i l a b l e . In l i g h t o f c u r r e n t knowledge t h i s could be a h i g h l y imprudent p u b l i c h e a l t h p o l i c y .

Rodricks and Tardiff; Assessment and Management of Chemical Risks ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

I.

Conceptual Basis for Risk Assessment

RODRICKS AMD TARDIFF

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If we f a i l to f i n d workable approaches to the problem of assessing chemical r i s k and f a i l to i d e n t i f y some systematic way to d e a l with these s c i e n t i f i c u n c e r t a i n t i e s , we would indeed f i n d o u r s e l v e s i n a s e r i o u s predicament. Thus, we would be faced with the prospect of not being able to decide whether exposure to a chemical can or can not be permitted, unless we base the d e c i s i o n on grounds completely unrelated to the question of r i s k . The l a t t e r course seems h i g h l y undesirable, although i t has sometimes been t a k e n . In the context of r e g u l a t o r y decision-making, the d i f f i c u l t i e s of d e f i n i n g the nature and magnitude of chemical r i s k can be overcome (indeed, have been for years) by the a p p l i c a t i o n of c e r t a i n o p e r a t i o n a l schemes. A p p l i c a t i o n of these schemes can not be claimed to lead to true estimates of human r i s k , yet there are good reasons to b e l i e v e that they meet the d e s i r a b l e c r i t e r i o n o f being capable of d i s t i n g u i s h i n g low from high r i s k exposures, and do so i n a systematic f a s h i o n . The major o p e r a t i o n a l schemes now i n use represent two s t r i k i n g l y d i f f e r e n t approaches to the problem of assessing the h e a l t h consequences o f chemical exposures, and we s h a l l now d e s c r i b e them. r

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T r a d i t i o n a l Safety Assessment Schemes The task o f a s s i g n i n g safe exposure l e v e l s f o r chemicals has t r a d i t i o n a l l y been assigned t o t o x i c o l o g i s t s . During the f i r s t h a l f o f t h i s century, t h i s problem arose i n connection with food a d d i t i v e s , p e s t i c i d e s , drugs, and o c c u p a t i o n a l exposures. Although toxicologists experimented with a variety of approaches, there emerged a scheme f o r a s s i g n i n g s a f e exposure l e v e l s that was based on the a p p l i c a t i o n of s a f e t y f a c t o r s to experimental t o x i c i t y data, d e r i v e d f o r the most p a r t from s t u d i e s i n animals, but a l s o from c o n t r o l l e d s t u d i e s i n v o l v i n g humans(jL) . In g e n e r a l , t o x i c o l o g i s t s would d i v i d e experimentally-determined "no-observed e f f e c t l e v e l s " (NOELs) by such safety factors. The l e v e l of exposure a r r i v e d a t by a p p l i c a t i o n o f s a f e t y f a c t o r s has never been claimed to be t o t a l l y without risk, but i t became widely accepted within the community o f toxicologists that t h i s type of scheme i s appropriate f o r d e f i n i n g acceptable human exposure levels (except for carcinogens — see below) . Thus arose the

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Thus, one approach to deciding how much exposure to a carcinogen can be permitted i s to s e t l i m i t s at whatever the d e t e c t i o n c a p a b i l i t y of a v a i l a b l e a n a l y t i c a l methods happens to be. The l a t t e r has, of course, no r e l a t i o n s h i p t o r i s k . This is

not

t o say

that a n a l y t i c a l

capabilities

as w e l l as

a host

other f a c t o r s should not play a r o l e i n decision-making. only to say that r i s k should not be ignored.

Rodricks and Tardiff; Assessment and Management of Chemical Risks ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

of

It is

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ASSESSMENT A N D M A N A G E M E N T OF C H E M I C A L RISKS

concepts of "acceptable d a i l y intake" (ADI) f o r food and c o l o r a d d i t i v e s and p e s t i c i d e s , and Permissible Exposure Limits (PELs) f o r exposures i n the workplace(1,2). The c e n t r a l concept underlying t h i s approach i s that f o r most forms of t o x i c i t y , the production of e f f e c t s requires a c e r t a i n minimum dose (a threshold dose), and that unless the minimum dose i s exceeded, no e f f e c t w i l l o c c u r ( 2 ) . The experimental NOEL may approximate such a threshold dose i n the small and r e l a t i v e l y homogeneous group of t e s t animals s t u d i e d . However, there are plausible biological reasons as w e l l as e m p i r i c a l evidence to show that the threshold dose i s not f i x e d ; t h a t i t v a r i e s , sometimes g r e a t l y , among i n d i v i d u a l s i n a population; and that some members of the human population may be more s u s c e p t i b l e than experimental animals t o the t o x i c e f f e c t s of chemicals. I t thus became the p r a c t i c e to apply s a f e t y f a c t o r s to NOELs i n order to compensate for these possibilities, for the other scientific u n c e r t a i n t i e s described e a r l i e r , and f o r l i m i t a t i o n s i n the q u a l i t y ôf the experimental d a t a ( 3 ) · T h i s s a f e t y assessment scheme, which i s s t i l l i n wide use, has never been claimed to provide absolute s a f e t y (zero risk)· There i s , i n f a c t , no scheme that could do so. But i t does c l a i m that any r e s i d u a l r i s k associated with exposures c o r r e s ponding t o an ADI i s almost c e r t a i n l y very low(!3) · This i s probably the case f o r most types o f t o x i c agents, but we have no method to determine whether i t i s . But because the scheme claims to provide an estimate of low r i s k exposures, i t i s , a t least implicitly, a r i s k assessment scheme that makes no attempt to c h a r a c t e r i z e the r i s k that remains at exposures s a i d t o be "acceptable". L i m i t a t i o n s In The

Safety Assessment Scheme

The s a f e t y assessment scheme described above appears to have provided adequate p u b l i c health p r o t e c t i o n , and w i l l no doubt continue i n use f o r some time to come. There are, however, c e r t a i n l i m i t a t i o n s i n the scheme that should be acknowledged. F i r s t , the use of ADIs (or t h e i r equivalent) tends to give the impression that exposures to chemicals are e i t h e r "safe" (below the ADI) or "unsafe" (above the ADI). Those who work i n the area know that t h i s i s a f a l s e i n t e r p r e t a t i o n , because r i s k to a population does not simply "disappear" at a given dose. In f a c t there may be f o r some agents a range of doses w e l l above t h e i r ADIs that f a l l w e l l w i t h i n the low or even zero r i s k category. On the other hand, r i s k may sometimes r i s e r a p i d l y through and above an ADI. The point i s that there are no sharp d i v i s i o n s i n the continuum of dose-risk r e l a t i o n s , a t least i n s o f a r as we are concerned with population, not individual, r i s k s ( 3 ) ·

Rodricks and Tardiff; Assessment and Management of Chemical Risks ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

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1.

RODRICKS A N D TARDIFF

Conceptual Basis for Risk Assessment

I t should be recognized t h a t , no matter what r i s k assessment scheme i s used, there w i l l f i n a l l y emerge an exposure l e v e l which w i l l be s a i d t o be acceptable. There w i l l probably always be a tendency t o view such " o f f i c i a l l e v e l s " as the dividing l i n e s between "safe" and "unsafe" exposures. We suggest, however, that the use o f a scheme that provides e x p l i c i t estimates o f r i s k , and from which policy-makers decide on the r i s k that i s t o l e r a b l e i n s p e c i f i c circumstances, i s less l i k e l y t o be m i s i n t e r p r e t e d as p r o v i d i n g such sharp distinctions. Procedures f o r estimating and using NOELs can be wasteful of data(J3f4) - The s e l e c t i o n o f the highest dose a t which "no e f f e c t " i s observed (the NOEL) ignores the p o s s i b i l i t y that the lack o f observed e f f e c t s could have been the r e s u l t o f chance v a r i a t i o n about a true e f f e c t . I f two experiments, i d e n t i c a l except f o r sample s i z e , y i e l d i d e n t i c a l NOELs, the l a r g e r experiment p r o v i d e s greater evidence that a true NOEL has been observed, and hence greater evidence o f s a f e t y . The NOEL approach a l s o does not f u l l y u t i l i z e the experimental doseresponse information. Dose-responses that decrease sharply with decreasing dose have d i f f e r e n t i m p l i c a t i o n s f o r r i s k s a t doses below the observed NOEL ( i . e . , the human dose) than do shallower dose responses. However, t h i s d i f f e r e n c e may not be accounted f o r i n the s e t t i n g of ADIs. Serious questions can a l s o be r a i s e d about the use o f s p e c i f i c " s a f e t y f a c t o r s " t o e s t a b l i s h ADIs without s c i e n t i f i c evidence t o support the magnitude o f such f a c t o r s . In f a c t , there i s nothing but custom t o support the use o f any s p e c i f i c s a f e t y f a c t o r {3_,5). Because i t can a l s o be reasonably argued that the s e l e c t i o n o f s p e c i f i c s a f e t y f a c t o r s i s a matter o f p o l i c y , not science, the s a f e t y assessment scheme can be seen as a blend o f s c i e n t i f i c and p o l i c y d e c i s i o n s that cannot be e a s i l y separated. I t appears, then, that some m o d i f i c a t i o n i n the "NOELs a f e t y f a c t o r " approach i s i n order. There are d i f f i c u l t i e s that must be overcome before we can a r r i v e at suitable a l t e r n a t i v e methods but i t i s time t o begin t o move away from the concept that t o x i c o l o g i s t s can decide what i s "safe" by simply s e l e c t i n g a r b i t r a r y "safety f a c t o r s " . We need t o f i n d ways t o use the dose-response information i n e s t a b l i s h i n g ADIs, and a l s o t o d i s t i n g u i s h e x p l i c i t l y the s c i e n t i f i c aspects o f these types o f analyses from the p o l i c y aspects. F i n a l l y , the scheme has g e n e r a l l y not been considered, even by i t s proponents, appropriate t o apply t o carcinogens. T h i s view may stem from the l e g a l s t r i c t u r e (which e x i s t s i n the United States i n the form o f the Delaney c l a u s e o f the Food, Drug and Cosmetic Act) that no ADI can be e s t a b l i s h e d f o r a c a r c i n o g e n i c a d d i t i v e , i n which case no s a f e t y assessment scheme i s needed. On the other hand, i t may stem from a s c i e n t i f i c view that the mode o f a c t i o n o f carcinogens i s such

Rodricks and Tardiff; Assessment and Management of Chemical Risks ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

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that exposure a t a c a l c u l a t e d ADI (experimental NOELs can be defined f o r many carcinogens) i s almost assuredly going to pose a r i s k o f cancer, r e g a r d l e s s of the magnitude o f the s a f e t y factor. Exposure to other types of t o x i c agents at a c a l c u l a t e d ADI w i l l , i n many cases, a l s o pose a f i n i t e r i s k . For both carcinogens and other types of t o x i c a n t s , i t i s not possible t o show r i g o r o u s l y that zero p o p u l a t i o n r i s k i s achieved a t any f i n i t e dose. I t i s p o s s i b l e , however, to estimate low or even n e g l i g i b l e r i s k doses f o r a l l forms of t o x i c a n t s , i n c l u d i n g carcinogens, although we suggest that the t r a d i t i o n a l methods f o r e s t a b l i s h i n g ADIs are probably not the best ways t o accomplish these g o a l s ( 4 ) .

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Newer Concepts Of Assessment I t i s c l e a r t h a t not a l l chemicals t h a t e x h i b i t c a r c i n o g e n i c p r o p e r t i e s can simply be banished from our s o c i e t y . I t has become necessary to e s t a b l i s h a systematic means f o r d e c i d i n g the extent t o which human exposure to carcinogens should be limited. I t was i n t h i s context that a d i s t i n c t l y d i f f e r e n t scheme was developed to e s t a b l i s h acceptable exposures. In i t s i d e a l i z e d form, t h i s scheme i n v o l v e s two major and distinct steps (6^) : (1) Risk assessment i s performed t o determine the nature and magnitude of r i s k a s s o c i a t e d with v a r i o u s l e v e l s and c o n d i t i o n s of human exposure to a carcinogen. (2) Risk management a n a l y s i s i s performed to decide the magnitude of r i s k that i s t o l e r a b l e i n s p e c i f i c circumstances ( i . e . , i n the context of c u r r e n t s t a t u t e s and v a r i o u s c o n t r o l o p t i o n s ) . Under t h i s scheme, a d e c i s i o n on acceptable exposures i s made i n the second step, and i n v o l v e s matters of p o l i c y q u i t e d i s t i n c t from those i s s u e s concerning the nature and magnitude of r i s k . Under t h i s scheme, the r o l e of the h e a l t h s c i e n t i s t i s f a r more r e s t r i c t e d than i t i s i n the t r a d i t i o n a l s a f e t y assessment d e s c r i b e d e a r l i e r . The health s c i e n t i s t i s no longer r e s p o n s i b l e f o r a s s i g n i n g acceptable exposures. On the other hand, the s c i e n t i s t has a more demanding task than under the t r a d i t i o n a l scheme, because he or she i s asked to make an e x p l i c i t statement about r i s k . This scheme appears t o have a number of d e s i r a b l e features. Most of a l l , i t r e q u i r e s r e c o g n i t i o n that science alone can not decide what i s safe or acceptable(6^) . (It must be acknowledged that many s c i e n t i s t s remain convinced that science can, indeed, make such d e c i s i o n s . We b e l i e v e t h i s i s an i n c o r r e c t view.) Further, i t r e q u i r e s that h e a l t h s c i e n t i s t s focus more d i r e c t l y on the e s s e n t i a l s c i e n t i f i c problems of risk assessment and come to g r i p s with a l l of those fundamental gaps i n knowledge described i n the opening s e c t i o n

Rodricks and Tardiff; Assessment and Management of Chemical Risks ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

I.

RODRICKS AND TARDIFF

Conceptual Basis for Risk Assessment

of t h i s paper. Under t h i s scheme, the r o l e o f s c i e n t i s t s i s thus t o : 1) d e f i n e the most rigorous and systematic approaches to assessing r i s k that can now be found and j u s t i f i e d , taking care t o d e s c r i b e a l l the u n c e r t a i n t i e s attendant upon t h i s task, so that some statement can be made about r i s k ; and 2) conduct the research necessary t o reduce these u n c e r t a i n t i e s . In other words, the r o l e o f the health s c i e n t i s t i s t o measure r i s k and a l s o t o d e s c r i b e and improve methods t o p r e d i c t r i s k s under c o n d i t i o n s o f exposure f o r which r i s k information can not be d i r e c t l y c o l l e c t e d .

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Risk Assessment Under the d e f i n i t i o n o f r i s k assessment we propose, i t i s a broad a c t i v i t y , by no means l i m i t e d t o the uncomfortable problem o f high-to-low dose e x t r a p o l a t i o n , which many people take i t t o b e ( j 5 ) . I t i n c l u d e s , as i t s f i r s t step, the problem of hazard identification and e v a l u a t i o n . In b r i e f , this problem i n v o l v e s review and e v a l u a t i o n o f v a r i o u s types o f experimental and e p i d e m i o l o g i c a l information f o r purposes o f identifying the nature o f the hazards a s s o c i a t e d with a substance or a c t i v i t y . I t i s designed t o answer questions such as: Is (substance x) a carcinogen? What type o f carcinogen i s it? What i s the l i k e l i h o o d that the experimentally observed carcinogenic response i s somehow uniquely r e l a t e d t o the c o n d i t i o n s o f experimental exposure? What i s the nature and strength o f the evidence supporting this evaluation? The s u c c e s s f u l execution o f t h i s step depends on a fundamental b e l i e f i n the u n i t y o f b i o l o g y , but i s a l s o dependent upon a realization that interspecies differences i n response are always p o s s i b l e and need t o be considered. The second step, termed dose-response e v a l u a t i o n , i n v o l v e s identifying the observed quantitative r e l a t i o n s h i p between exposure and r i s k , and e x t r a p o l a t i n g from the c o n d i t i o n s o f exposure f o r which data exist t o other conditions of i n t e r e s t ( ( 5 ) . T h i s step almost always i n v o l v e s high-to-low dose extrapolation and frequently involves extrapolation from experimental animals t o humans. This step r e q u i r e s the assumption that dose-response r e l a t i o n s do not simply disappear at the d e t e c t i o n l i m i t o f our experimental or epidemiologic systems. I t also requires that a biologically plausible mathematical f u n c t i o n be employed t o c h a r a c t e r i z e the low end of the dose-response curve. F i n a l l y , i t f r e q u e n t l y requires the imposition o f assumptions regarding the q u a n t i t a t i v e r e l a t i o n s h i p between t e s t animal dose-response f u n c t i o n s and those expected t o apply t o human populations. The t h i r d step i s i d e n t i f i c a t i o n o f the c o n d i t i o n s o f exposure (broadly defined t o include i n t e n s i t y , frequency and duration) o f the human population group that might be a t r i s k and f o r which p r o t e c t i o n i s sought{6). The l a s t step i n v o l v e s

Rodricks and Tardiff; Assessment and Management of Chemical Risks ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

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combining the information on dose-response with that on exposure t o d e r i v e estimates o f the p r o b a b i l i t y that the hazards a s s o c i a t e d with a substance or a c t i v i t y w i l l be r e a l i z e d under the c o n d i t i o n s o f exposure experienced by the p o p u l a t i o n group of interest. Risk assessment i n v o l v e s i n t e g r a t i o n o f the information and a n a l y s i s a s s o c i a t e d with these four steps t o provide a complete c h a r a c t e r i z a t i o n o f the nature and magnitude of r i s k and the degree o f confidence a s s o c i a t e d with t h i s characterization. A c r i t i c a l component o f the assessment i s a f u l l e l u c i d a t i o n o f the u n c e r t a i n t i e s a s s o c i a t e d with each o f the major s t e p s ( 6 ) . Under t h i s broad concept o f r i s k assessment are encompassed a l l o f the e s s e n t i a l problems o f t o x i c o l o g y that t r a d i t i o n a l s a f e t y assessment schemes have d e a l t w i t h but they have been recast t o provide a means f o r answering a d i f f e r e n t question — t h a t i s , the question o f r i s k . There are other important d i f f e r e n c e s as w e l l . Risk assessment does not r e l y on the b i o l o g i c a l l y and s t a t i s t i c a l l y dubious concept o f a NOEL, but takes i n t o account a l l o f the a v a i l a b l e dose-response data. I t treats u n c e r t a i n t y not by the a p p l i c a t i o n o f a r b i t r a r y s a f e t y f a c t o r s , but by s t a t i n g them i n q u a l i t a t i v e l y and q u a n t i t a t i v e l y e x p l i c i t terms, so that they are not hidden from decision-makers. Risk assessment d e f i n e d i n t h i s broad way f o r c e s an assessor t o confront a l l the s c i e n t i f i c uncert a i n t i e s and t o s e t f o r t h i n e x p l i c i t terms the means used i n s p e c i f i c cases t o d e a l with these u n c e r t a i n t i e s . And, o f course, r i s k assessment does not i n c l u d e those decision-making processes necessary t o e s t a b l i s h acceptable exposure c o n d i t i o n s .

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Risk Management Completion o f a r i s k assessment y i e l d s no view o f whether the p r o j e c t e d r i s k s are important and r e q u i r e the i m p o s i t i o n o f c o n t r o l s . We here enter the realm o f r i s k management, which i s far l e s s well-developed than even the f r a g i l e domain o f r i s k assessment(3^. Some contend that r i s k management d e c i s i o n s are s t r i c t l y matters o f p o l i c y . We do not argue t h i s p o i n t , but add that t h i s does not mean they should be devoid o f o b j e c t i v e , a n a l y t i c support. The problem seems t o have two primary components. The f i r s t i n v o l v e s a d e c i s i o n on whether or not the assessed r i s k i s important. T h i s d e c i s i o n , we suggest, should not be based s o l e l y on the magnitude o f the p r o j e c t e d r i s k , but a l s o on the degree o f confidence that can be placed i n both the data underlying the assessment and the methods and assumptions used. The degree o f confidence i s a f u n c t i o n o f s e v e r a l aspects o f the assessment, i n c l u d i n g the strength o f the evidence supporting the c o n c l u s i o n that a substance i s indeed hazardous (e.g., that a chemical i s a human carcinogen), the extent t o which supporting data are b i o l o g i c a l l y and s t a t i s t i c a l l y concordant, and the extent o f

Rodricks and Tardiff; Assessment and Management of Chemical Risks ACS Symposium Series; American Chemical Society: Washington, DC, 1984.

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v a r i a b i l i t y i n the r i s k when i t i s p r e d i c t e d under d i f f e r e n t assumptions and models. Some means i s needed t o permit systematic c o n s i d e r a t i o n o f a l l o f these types o f information i n the decision-making process, but l i t t l e a n a l y t i c work has y e t been done i n t h i s area. Some agencies have d e f i n e d n e g l i g i b l e or de minimis r i s k f o r some carcinogens s t r i c t l y i n q u a n t i t a t i v e terms(2) · This approach may be a reasonable place t o s t a r t a n a l y s i s , but i t f a i l s t o recognize that the data bases f o r d i f f e r e n t c a r c i n o gens vary widely i n q u a l i t y and content, and that s e v e r a l other non-quantifiable factors (that we i n c l u d e as p a r t of the assessment o f "degree o f confidence") i n f l u e n c e the r i s k . In other terms, two substances apparently posing the same q u a n t i t a t i v e r i s k may, i n f a c t , produce q u i t e d i f f e r e n t r i s k s . We suggest that the other non-quantitative information a v a i l a b l e i n the r i s k assessment can serve as a guide t o determining the l i k e l i h o o d o f such d i f f e r e n c e s . If i t i s decided that a r i s k i s worth worrying about, a d d i t i o n a l a n a l y s i s i s needed t o decide how and t o what extent c o n t r o l i s necessary. T h i s area i n v o l v e s questions o f c o s t , t e c h n i c a l f e a s i b i l i t y , and law, a l l o f which we leave t o o t h e r s . Conclusion The s a f e t y assessment scheme now a p p l i e d t o t o x i c agents other than carcinogens c o u l d be modified so that b e t t e r advantage i s taken o f dose-response information and so t h a t s c i e n t i f i c aspects o f the scheme can be d i s t i n g u i s h e d from the p o l i c y aspects. D e c i s i o n s on appropriate s a f e t y f a c t o r s , i f needed, would be a s s o c i a t e d with the domain o f policy-making, t h e i r magnitude depending on scientific judgments regarding u n c e r t a i n t i e s i n the data and dose-response r e l a t i o n s . As c u r r e n t l y p r a c t i c e d r i s k assessment i s c o n c e p t u a l l y sound, but the u n c e r t a i n t i e s are great because o f gaps i n fundamental knowledge. Research i n t o underlying mechanisms o f t o x i c i t y , as they bear on knowledge o f dose-response relations at low dose, i s c r i t i c a l t o further advances i n t h i s f i e l d . C l e a r l y the h i g h l y i n s e n s i t i v e research t o o l s we now have cannot be r e l i e d upon i n d e f i n i t e l y as the b a s i s f o r these important p u b l i c h e a l t h d e c i s i o n s .

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RECEIVED November 4, 1983

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