Human Risk Assessment from Animal Data - ACS Symposium Series

31 Human Risk Assessment from Animal Data

Downloaded by UNIV OF CALIFORNIA SANTA BARBARA on May 16, 2018 | https://pubs.acs.org Publication Date: August 10, 1981 | doi: 10.1021/bk-1981-0160.ch031

ROBERT A. SQUIRE Division of Comparative Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205

A forum entitled "Animal Tests and Human Cancer" was reported in Chemical and Engineering News, June 27, 1977, with an eye-catching cover photo of a rat. The forum was prompted by the proposed ban on saccharin following the Canadian study which showed the induction of bladder cancer in rats. For the first time, it appeared the public was acutely aware of the impact of governmental regulatory legislation upon their personal lives. The possibility of this ban has stimulated widespread awareness and uncertainty about regulatory policies, and raised many questions about the state of the art in animal testing. There are three fundamental methods for estimating potential human risk as the result of exposure to toxic substances, whether the exposure be from food, drugs, air, water or the workplace. These are: (l) epidemiological studies, (2) animal tests, and (3) short-term or in vitro analyses such as studies of DNA damage or mutagenesis. Of the three methods, the greatest confidence is placed upon epidemiological studies in humans. Unfortunately, however, epidemiology is limited in its sensitivity and its application to toxicity assessment. The g r e a t e s t value has derived from r e c o g n i t i o n o f occupational hazards where there i s high exposure to w e l l defined human p o p u l a t i o n s , o r from studies l i k e those on c i g a r e t t e smoking, where exposure may be c l e a r l y d e f i n e d . However, i n the case o f more u b i q u i t o u s , i l l - d e f i n e d and low l e v e l exposure to toxic substances, observations i n humans often l a c k the s e n s i t i v i t y to d i s c e r n p o s s i b l e toxic e f f e c t s . We are l e f t then with the next a l t e r n a t i v e , the use o f other mammalian species as human surrogates. I n t a c t mammalian systems are considered most r e l e v a n t to human r i s k because no other methods can simulate the complex b i o l o g i c a l systems which allow us to survive and even t h r i v e i n an environment r e p l e t e with n a t u r a l and man-made chemical poisons as w e l l as harmful p h y s i c a l and b i o l o g i c a l agents. There i s an e f f i c i e n t homeos t a t i c apparatus i n the i n t a c t animal system which determines the safe versus t o x i c l e v e l s o f exogenous substances.

0097-6156/81/0160-0493$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.

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Table I R a t i o n a l e f o r Use o f Animals i n T o x i c o l o g i c a l T e s t i n g 1.

Mammals are anatomically, biochemically s i m i l a r .

2.

Mammals have s i m i l a r h e a l t h and disease and causes.

3·

Mammals 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 ( d i f f e r e n c e s are p r i m a r i l y q u a n t i t a t i v e r a t h e r than q u a l i t a t i v e ) .

p h y s i o l o g i c a l l y and

manifestations

The three statements i n Table I are simple and a x i o m a t i c They form the b a s i s f o r a l l o f the comparative medicine, and the use of animals i n medical research and i n t o x i c o l o g i c a l and c a r c i n o g e n i c i t y t e s t i n g . They are however, broad g e n e r a l i z a t i o n s o f b i o l o g i c a l t r u t h s . They do not n e c e s s a r i l y apply i n every instance nor do they t e l l us which species i s most s i m i l a r to human. I t i s g e n e r a l l y impossible to p r e d i c t how any given species or i n d i v i d u a l w i l l respond to a p o t e n t i a l l y t o x i c substance without d e t a i l e d metabolic and pharmacokinetic s t u d i e s . Despite proclamations to the c o n t r a r y by some s c i e n t i s t s , p o l i t i c i a n s , lawyers and others, the e x t r a p o l a t i o n o f animal t o x i c i t y data to human r i s k assessment, although necessary i n the r e g u l a tory sense, i s o f t e n based upon s e v e r a l unproven assumptions. I t i s t h i s very u n c e r t a i n t y which allows and encourages d i v e r s e and opposing claims, p r e d i c t i o n s and warnings from those advocating one or another viewpoint, since most o f the c l a i m s , no matter how extreme, cannot be proven o r disproven. L i t i g a t i o n proceedings and hearings have not, i n my view, provided the most e f f i c i e n t o r r a t i o n a l means to r e s o l v i n g these questions. I t i s p a r t i c u l a r l y true with respect to the assessment o f carcinogenic r i s k s that we have had to place v i r t u a l l y complete r e l i a n c e upon e x t r a p o l a t i o n from animal t e s t s . T h i s has r e s u l t e d in the r e s t r i c t i o n o f use o r removal from the marketplace o f s e v e r a l chemical substances i n c l u d i n g p e s t i c i d e s - such as DDT, A l d r i n , D i e l d r i n , Chlordane and Heptachlor. Other p e s t i c i d e s and chemicals already i n use have a l s o been found to be carcinogenic to one or more animal species i n the N a t i o n a l Cancer I n s t i t u t e t e s t i n g program - now part o f the N a t i o n a l Toxicology Program. I t i s probably safe to assume that such animal t e s t i n g a c t i v i t i e s w i l l increase, a t l e a s t f o r the immediate f u t u r e . Since we have learned that f i n d i n g a c a r c i n o g e n i c response i n a t e s t animal may t r i g g e r d e c i s i o n s which have f a r reaching impact on our s o c i e t y and economy, i t i s u s e f u l to examine some of the procedures involved i n e v a l u a t i n g t o x i c o l o g i c a l data and estimating p o t e n t i a l human r i s k . In doing so, i t should become apparent that s e v e r a l areas o f u n c e r t a i n t y and p o t e n t i a l e r r o r

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


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can i n f l u e n c e major regulatory d e c i s i o n s and mislead an uninformed p u b l i c . Although the procedures could be discussed i n many ways, I have chosen to use four main c a t e g o r i e s : ( l ) v a l i d i t y o f animal data; (2) weight o f t o x i c o l o g i c a l evidence; (3) c h a r a c t e r i s t i c s of the test substance; and f i n a l l y , (h) q u a n t i t a t i v e r i s k assessment. The f i r s t step i s to insure that the evidence that a substance a c t u a l l y i s an animal carcinogen i s s u f f i c i e n t and persuasive. The degree o f evidence f o r animal c a r c i n o g e n i c i t y v a r i e s c o n s i d e r a b l y from very weak to overwhelming, but t h i s aspect i s often overlooked when a p o s i t i v e f i n d i n g i s reported. The next two c a t e g o r i e s , the weight o f t o x i c o l o g i c a l evidence and the chemical and b i o l o g i c a l c h a r a c t e r i s t i c s o f the test substance, can d i s c r i m i n a t e among the r e l a t i v e potencies o r v i r u l e n c e o f p o t e n t i a l human carcinogens and h o p e f u l l y d i s p e l l the impression that a l l animal carcinogens pose equal t h r e a t s to man. L a s t l y , I w i l l b r i e f l y discuss q u a n t i t a t i v e r i s k assessment which attempts to p r e d i c t a numerical incidence o r range o f potent i a l toxic or carcinogenic responses i n the human p o p u l a t i o n . The v a l i d i t y o f the animal data addresses not only the accuracy o f the f i n d i n g s but a l s o the relevance o f the e x p e r i mental data f o r man. I f comparative metabolic o r pharmacokinetic studies r e v e a l a q u a n t i t a t i v e d i f f e r e n c e between the t e s t animal and human responses o r routes o f exposure, the f i n d i n g s may t o t a l l y l a c k p r e d i c t i v e value. Such s t u d i e s are r a r e l y performed because o f the l i m i t a t i o n s imposed by time and funding; thus there i s u s u a l l y no a l t e r n a t i v e but to e r r on the side o f prudence and accept p o s i t i v e animal f i n d i n g s . Unless there i s e v i dence to the c o n t r a r y , a r e g u l a t o r has no choice but to assume that test animal data may be p r e d i c t i v e o f the response among a t l e a s t some i n d i v i d u a l s i n the heterogeneous human p o p u l a t i o n . Dose l e v e l s employed p a r t i c u l a r l y i n c a r c i n o g e n e s i s t e s t i n g remain an area o f controversy. The r a t i o n a l e f o r the maximum t o l e r a t e d dose concept i s based i n part upon the i n s e n s i t i v i t y o f t e s t s which use small numbers o f animals as compared to the l a r g e human population a t r i s k . T h i s i s a v a l i d t o x i c o l o g i c a l premise f o r safety t e s t i n g provided we assume the phenomenological events i n c a r c i n o g e n e s i s are dose r e l a t e d i n a r e l a t i v e l y l i n e a r f a s h i o n . That i s , the pharmacokinetics, metabolism, extent o f DNA damage versus r e p a i r , e t c . are d i r e c t l y p r o p o r t i o n a l to the dose; that toxic e f f e c t s observed a t high t e s t doses a c c u r a t e l y p r e d i c t , 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 , the e f f e c t s a t a c t u a l low exposure l e v e l s . We have heard and read much about t h i s issue f o r some time, and i t i s the b a s i s f o r controversy surrounding not only the choice o f the maximum t o l e r a t e d dose but a l s o the s e l e c t i o n o f mathematical models when attempting to p r e d i c t s p e c i f i c l e v e l s o f human r i s k . In t r u t h , the f a c t s are u s u a l l y not known since the necessary experiments are not performed. The



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choice of the high test dose, l i k e that o f mathematical models, i s based more upon c o n v i c t i o n or theory than upon s c i e n t i f i c e v i dence, and yet these are two o f the most important f a c t o r s i n e x t r a p o l a t i n g animal r e s u l t s to human r i s k . There are known animal carcinogens, or tumor inducers, i f you p r e f e r , which probably would not have been detected i f animals had been treated at doses which were not o v e r t l y t o x i c . So, an important question i s : Do we r e a l l y want to know i f something can cause cancer i n animals at very high doses, even i f they are considered excessive or unphysiologic? I think i t important to have t h i s information so I do not o b j e c t to high t e s t doses. But, i n using t h i s information to e x t r a p o l a t e to human r i s k , a d d i t i o n a l f a c t o r s should a l s o be considered other than the f a c t that a substance can induce cancer i n test animals. Next, I cannot f a i l to s t r e s s the importance and the potent i a l e r r o r s involved in the p a t h o l o g i c e v a l u a t i o n . In the present p o l i t i c a l climate a carcinogen may be i d e n t i f i e d or obscured because there i s a s t a t i s t i c a l l y s i g n i f i c a n t d i f f e r e n c e in one or more tumor types i n treated animals as compared to cont r o l animals. The process, thus, may amount to a numbers game rather than a r e l i a n c e upon the biomedical judgment which i s r e q u i r e d . P a r t i c u l a r l y important i s knowledge o f the spontaneous diseases i n l a b o r a t o r y animals, a s p e c i a l t y f i e l d i n i t s e l f . Proper p a t h o l o g i c a l e v a l u a t i o n r e q u i r e s a r e l a t i v e l y comp l e t e and, above a l l , uniform examination o f t i s s u e s i n treated and c o n t r o l groups i n order to determine a c t u a l tumor i n c i d e n c e s . In past research studies d e a l i n g with known, strong carcinogens, pathologic accuracy was l e s s important. S i m i l a r l y today, i f t e s t compound X turns out to be a strong carcinogen, t h i s f a c t w i l l be r e a d i l y apparent — probably as e a r l y as the necropsy examinat i o n s before any p r e c i s e t i s s u e counts or h i s t o l o g i c examinations are performed. However, when t r y i n g to d i s c e r n weak carcinogens from non-carcinogens, as most chemical t e s t i n g now attempts to do, the a d d i t i o n or s u b s t r a c t i o n o f very few tumors from any one animal test group or another can s t a t i s t i c a l l y create a safe substance or a carcinogen! R e a l i z e that aged c o n t r o l mice and r a t s may have high and v a r i a b l e spontaneous tumor r a t e s , v a r y i n g i n some t i s s u e s from 5-h0% among d i f f e r e n t c o n t r o l groups. These d i f f e r e n c e s may be h i g h l y s i g n i f i c a n t , and undoubtedly r e s u l t from the many e n v i r o n mental modifying f a c t o r s which i n f l u e n c e tumor i n c i d e n c e s . T h i s emphatically p o i n t s out the p o s s i b i l i t y o f spurious r e s u l t s i n some c a r c i n o g e n e s i s t e s t s . The subject o f f a l s e p o s i t i v e and f a l s e negative r e s u l t s i n i d e n t i f y i n g weak animal carcinogens, t h e r e f o r e , r e q u i r e s more r e c o g n i t i o n and e v a l u a t i o n than i t has received. Another important issue i s that the d i a g n o s t i c terms used by p a t h o l o g i s t s determine how many o f each type o f p r e n e o p l a s t i c l e s i o n s or of benign or malignant tumors i s reported. On the



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b a s i s o f pathogenesis or e t i o l o g y some d i f f e r e n t tumor types should be lumped together for assessment o f carcinogenic e f f e c t s and others should not be. T h i s , o f course, i s c r i t i c a l to the s t a t i s t i c a l a n a l y s i s and the f i n a l c o n c l u s i o n . These are medical d e c i s i o n s which must be made by the p a t h o l o g i s t s on a case-bycase b a s i s , and i f there i s controversy surrounding the d i a g n o s i s , o r i f a s i g n i f i c a n t r e g u l a t o r y d e c i s i o n r e s t s upon the pathologic c l a s s i f i c a t i o n o f c e r t a i n l e s i o n s , then a peer review with consensus i s e s s e n t i a l . The scope and impact o f such d e c i sions requires that the pathologic i n t e r p r e t a t i o n s not be l e f t to a c o n t r a d i c t o r y testimony or a s i n g l e judgment. F i n a l l y , f o l l o w i n g the enumeration o f pathologic diagnoses, the choice o f the s t a t i s t i c a l model can, i n i t s e l f , a f f e c t the conclusion. This i s e s p e c i a l l y true i n d i s c e r n i n g a negative from a weak p o s i t i v e e f f e c t . Thus, before we even approach the area o f human r i s k assessment, o r e x t r a p o l a t i o n , the complex t e s t r e q u i r e d to determine whether or not a chemical i s an animal carcinogen, i . e . , the b a s i s f o r the q u a l i t a t i v e d e c i s i o n , i s already encumbered by many p o s s i b l e e r r o r s o f procedure o r judgment. Table I I Weight o f Evidence from Test Animal Data 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 Latency periods Dose-response r e l a t i o n s h i p s Nature ( s e v e r i t y ) o f l e s i o n s induced Table I I represents an important aspect o f animal to human e x t r a p o l a t i o n . These f i v e p o i n t s are, to me, the b i o l o g i c a l parameters which best determine the potency o r v i r u l e n c e o f an animal carcinogen, which i s to say the potency o f a human c a r cinogen according to current r e g u l a t o r y p o l i c i e s . To ignore t h i s type o f information, which i s o f t e n done, and consider a l l animal carcinogens as equal threats to man i s l u d i c r o u s i n l i g h t o f our knowledge. We know that there i s wide v a r i a t i o n i n species and t i s s u e s u s c e p t i b i l i t y to carcinogens. However, the more animal species which are s u s c e p t i b l e the more confident we may be that man i s l i k e l y to be s u s c e p t i b l e rather than unique i n h i s response. We a l s o know that c a r c i n o g e n i c response i s dose and time r e l a t e d , and that some carcinogens induce more malignant tumors than others. Thus, unless there i s evidence to the cont r a r y , the highest degree o f p o t e n t i a l human hazard should be a t t r i b u t e d to chemicals which induce p r i m a r i l y malignant tumors, at m u l t i p l e s i t e s , i n short periods o f time, a t low doses, and i n both sexes o f s e v e r a l species. I f the type o f induced tumor i n the animals i s normally r a r e , t h i s should a l s o be taken i n t o c o n s i d e r a t i o n since the enhancement o f tumors with g e n e t i c a l l y determined high spontaneous frequency may a l s o be accomplished by



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numerous d i e t a r y and other environmental m o d i f i e r s which are not i n themselves c a r c i n o g e n i c . Conversely the l e a s t concern might be a t t r i b u t e d to a chemical which, a f t e r m u l t i p l e species t e s t s , i s found to only enhance the incidence o f common tumors, i n one s i t e , i n one sex and s p e c i e s , and only f o l l o w i n g long exposure a t high and t o x i c dose l e v e l s . Table I I I d e s c r i b e s the c h a r a c t e r i s t i c s o f the test substance to be considered. Although i n the case o f c a r c i n o g e n e s i s , we do not know the mechanisms i n v o l v e d , there are inherent b i o l o g i c a l and chemical p r o p e r t i e s which can i n d i c a t e l i m i t s to the p o t e n t i a l r e a c t i v i t y o f chemicals with mammalian c e l l c o n s t i t u e n t s . These include chemical s i m i l a r i t y to other known t o x i n s , binding or adduct formation with c e l l macromolecules, g e n o t o x i c i t y or a c t i v i t y i n short-term t e s t s f o r c a r c i n o g e n i c i t y , metabolic and pharmacokinetic data, and other p e r t i n e n t p h y s i o l o g i c a l , pharmacological or biochemical p r o p e r t i e s . Table I I I C h a r a c t e r i s t i c s o f T e s t Substance Chemical s i m i l a r i t y to other known t o x i n s Binding to DNA, RNA, p r o t e i n G e n o t o x i c i t y or a c t i v i t y i n short-term t e s t s f o r carcinogenicity Metabolic and pharmacokinetic data P h y s i o l o g i c a l , pharmacological, and biochemical properties Unless we are to ignore a l l o f our h e a v i l y financed research on c a r c i n o g e n e s i s to date, we must assume that b i o l o g i c a l l y i n e r t substances, and those i n which the parent compound or i t s metabol i t e s do not a l t e r DNA, are not genotoxic and do not induce c e l l transformation, are not l i k e l y to be genetic-type carcinogens. I f they do induce tumors, i t can hardly be by a o n e - h i t , mutag e n i c - l i k e event, but rather by non-genetic mechanisms i n c l u d i n g chronic t i s s u e i n j u r y . T h i s type o f _in v i t r o and biochemical data, together with the weight o f evidence from animal t e s t r e s u l t s can c o n t r i b u t e to a r a t i o n a l b a s i s f o r r e g u l a t o r y judgment. F i n a l l y , there i s the area o f q u a n t i t a t i v e r i s k assessment (Table I V ) . T h i s subject has r e c e n t l y assumed an importance and prominence which tend to obscure the u n d e r l y i n g ignorance involved. Such procedures are attempts to p r e d i c t the magnitude or incidence o f t o x i c o l o g i c a l responses i n humans at low l e v e l s of exposure based upon responses observed i n animals a t high l e v e l s o f exposure. Assumptions, again which are l a r g e l y t h e o r e t i c a l , must be made concerning not only high to low dose e x t r a p o l a t i o n but a l s o concerning i n t e r s p e c i e s e x t r a p o l a t i o n .


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Table IV Q u a n t i t a t i v e Risk Assessment


1. 2. 3·

S e n s i t i v i t y o f test animals versus humans A r b i t r a r y safe f a c t o r s B i o l o g i c a l assumptions and mathematical models a. one-hit b. multi-hit c. multi-stage

The reason we are s t r u g g l i n g i n t h i s area i s that the mechanisms o f c a r c i n o g e n e s i s remain obscure. We simply do not know what the b i o l o g i c a l events or r i s k s are a t low l e v e l exposures to carcinogens where most human exposure occurs, and which i s beyond the s e n s i t i v i t y o f test animal observations. Thus, f o r example, thresholds or n o - e f f e c t l e v e l s cannot be proven o r d i s proven, and we do not know which mathematical model i s best, o r even i f any come c l o s e to r e f l e c t i n g the a c t u a l b i o l o g i c a l process. The primary advantage o f e x t r a p o l a t i o n using mathematical models i s that i t avoids the n e c e s s i t y o f debating a n o - e f f e c t o r threshold l e v e l , which cannot be s c i e n t i f i c a l l y documented. Rather i t provides an estimate o f r i s k which can be judged as acceptable or unacceptable and such a d e c i s i o n i s a s o c i e t a l rather than a s c i e n t i f i c one. The one-hit, m u l t i - h i t or multi-stage mathematical models l i s t e d i n Table IV r e f l e c t the range o f current t h e o r i e s surrounding the molecular events i n c a r c i n o g e n e s i s . The one-hit model presumes that a s i n g l e mutagenic-like event can i n i t i a t e the n e o p l a s t i c process. This implies a l i n e a r dose-response r e l a t i o n s h i p a t low a c t u a l exposure l e v e l s and thus u s u a l l y r e s u l t s i n a p r e d i c t i o n o f the highest incidences o f cancer and the lowest acceptable exposure l e v e l s o f a chemical. The m u l t i h i t and multi-stage models, on the other hand, do not a p r i o r i assume a one-hit mechanism a t any exposure l e v e l . A c r i t i c a l f a c t o r i n the assumption o f low-dose l i n e a r i t y i s the background o f spontaneous tumor o r disease r a t e s , i . e . an a d d i t i v e e f f e c t from exposure to m u l t i p l e carcinogens. Thus, the carcinogenic responses i n the l i v e r o r lymphoreticular systems o f mice g e n e r a l l y give a l i n e a r response r e g a r d l e s s o f the model employed. But mice have extremely high spontaneous r a t e s o f l i v e r cancer and lymphoma, and i t must be assumed that there i s a s i g n i f i c a n t population o f i n i t i a t e d or transformed c e l l s i n the mouse whether they be v i r u s induced or otherwise. One cannot n e c e s s a r i l y assume a s i m i l a r process i n humans, since no cancer incidence approximates those o f the l i v e r o r lymphoreticular systems i n mice. Conversely, however, one perhaps could expect a l i n e a r or even a concave response i n some humans exposed to a new animal lung carcinogen as the r e s u l t o f the high e x i s t i n g lung cancer r a t e . The important point here again i s that a l l p o s i t i v e



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animal c a r c i n o g e n e s i s data do not n e c e s s a r i l y i n d i c a t e equal human hazard. The many f a c t o r s I have o u t l i n e d should he considered when estimating p o t e n t i a l human r i s k , i n c l u d i n g the choice o f a mathematical model which best r e f l e c t s the t o t a l b i o l o g i c a l and chemical evidence a v a i l a b l e concerning the substance i n question. And i n l i g h t o f our recent experience with mathematical p r e d i c t i o n s as they r e l a t e to animal tumor s t u d i e s , the e x i s t i n g background o f tumors i n s p e c i f i c t i s s u e s i n humans should perhaps r e c e i v e g r e a t e r a t t e n t i o n i n q u a n t i t a t i v e r i s k assessments and r e g u l a t o r y d e c i s i o n s . One f i n a l point i s the s e n s i t i v i t y o f t e s t animals versus humans. C e r t a i n committees and i n d i v i d u a l s have, on the b a s i s o f very few comparative o b s e r v a t i o n s , expressed the view that humans are g e n e r a l l y more s u s c e p t i b l e than the test animals, since c a r cinogenic response appears to be d i r e c t l y p r o p o r t i o n a l to t o t a l c a r c i n o g e n i c dose. Inasmuch as humans l i v e l o n g e r , p o t e n t i a l exposure, and thus cancer r i s k , i s assumed to be greather than observed i n test animals. In answer to t h i s , note that the spontaneous cancer and other disease r a t e s i n aged or 2 year o l d mice and r a t s are comparable to those i n man a t 70 years o f age. Assuming that most cancers are, i n the broad sense, environmental diseases i n both man and animals, as the evidence s t r o n g l y supports, i t may be equally or more p l a u s i b l e to assume that the s e n s i t i v i t y of rodents i s g r e a t e r i f c a r c i n o g e n i c response depends upon t o t a l exposure, since they only l i v e a f r a c t i o n o f the human l i f e s p a n . The same i n f e r e n c e can be drawn from other mammalian species. Degenerative diseases and cancer reach high l e v e l s at the end o f t h e i r n a t u r a l l i f e s p a n s . Such responses therefore seem to depend upon b i o l o g i c a l processes which are not time r e l a t e d i n the absolute sense. In summary, I would l i k e to s t r e s s s e v e r a l p o i n t s . Extrapol a t i o n from experimental c a r c i n o g e n e s i s data to human r i s k i s e s s e n t i a l . Aside from the l i m i t e d information d e r i v e d from human e p i d e m i o l o g i c a l s t u d i e s , i t i s the o n l y means o f r e g u l a t i n g c a r cinogens. However, our present p o l i c i e s may not be the best to serve the p u b l i c i n t e r e s t . They t h r i v e on the c r i t i c a l areas o f s c i e n t i f i c ignorance i n t h i s f i e l d , and, u n f o r t u n a t e l y , there i s much to be gained — f i n a n c i a l l y , p r o f e s s i o n a l l y , and p o l i t i c a l l y — by e x p l o i t i n g some of the u n c e r t a i n t i e s which e x i s t . I f the p u b l i c were f u l l y aware o f the u n c e r t a i n t i e s rather than being confused by c o n f l i c t i n g c l a i m s , each sounding as i f i t were a proven f a c t , our cancer education and prevention e f f o r t s might be more e f f e c t i v e i n the long run. We cannot continue to propagate the notion that a l l animal carcinogens are e q u a l l y hazardous any more than a l l other toxins are e q u a l l y hazardous. T h i s t o t a l l y discourages any attempts by i n d i v i d u a l s i n s o c i e t y to p r i o r i t i z e and d i s c r i m i n a t e i n t h e i r own r i s k / b e n e f i t analyses, and the p u b l i c should c l e a r l y have t h i s p r i v i l e g e . Much of the misinformation admittedly i s the r e s u l t o f media coverage and s e n s a t i o n a l i s m . But i t should be



31.

SQUIRE

Human

Risk

Assessment

501

the r e s p o n s i b i l i t y at l e a s t o f government agencies to c o r r e c t t h i s by proper e d u c a t i o n a l e f f o r t s . The p u b l i c canot d i s c r i m i nate between press r e l e a s e s which announce p o s i t i v e c a r c i n o g e n i c f i n d i n g s unless the r e l a t i v e weights o f evidence are a l s o prominently presented i n an understandable manner. As I have pointed out, there are many types and l e v e l s o f animal evidence to be weighed, and when combined with genotoxic, biochemical and other data — we see a whole spectrum o f evidence f o r c a r c i n o g e n i c p o t e n t i a l . No r i g i d system o f c l a s s i f i c a t i o n o r of r e g u l a t i o n can accommodate these b i o l o g i c a l v a r i a b l e s . We can and should attempt to rank carcinogens by the nature and extent o f the experimental data i n mammalian and in v i t r o systems. T h i s ranking based upon a spectrum o f b i o l o g i c a l evidence, together with the use o f mathematical models, when a p p r o p r i t e , can provide a more r a t i o n a l b a s i s f o r q u a n t i t a t i v e r i s k assessment on a case-by-case b a s i s . RECEIVED March 12, 1981.


Human Risk Assessment from Animal Data - ACS Symposium Series

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