Assessing Environmental RiskâScientifically Defensible or Fantasy?

1 Assessing Environmental Risk— Scientifically Defensible or Fantasy? Vernon N. Houk

Downloaded by 80.82.77.83 on May 30, 2018 | https://pubs.acs.org Publication Date: May 5, 1994 | doi: 10.1021/ba-1994-0241.ch001

National Center for Environmental Health and Injury Control, Centers for Disease Control, Public Health Service, U . S . Department of Health and H u m a n Services, Atlanta, GA 30333

Estimating

the risk to human health from synthetic toxic substances

is becoming increasingly critical in our society. Epidemiological

stud-

ies should play a vital role in risk assessment. Without human data based on valid, well-done epidemiological studies, extrapolation from animal studies may seriously overestimate or underestimate the risk. To assess risk to the best of our ability, scientists must use all the data—human

and animal—and

combine this information

with the

soundest professional judgment. The multistage linearized model for quantitative risk assessment is not appropriate

for all chemicals and

just because the results of an epidemiological study have been published, they do not necessarily provide the final answers.

E S T I M A T I N G T H E RISK TO H U M A N H E A L T H from synthetic toxic s u b stances is i n c r e a s i n g l y c r i t i c a l i n o u r society. T h e t e r m "toxic substances" m a y b e a m i s n o m e r . T h e s e substances have c e r t a i n toxic effects o n animals a n d h u m a n s exposed to large amounts. H o w e v e r , for m a n y i f not most of these substances, the effects of l o w - l e v e l , c h r o n i c exposure r e m a i n u n k n o w n or may b e o n l y b i o l o g i c a l , s u c h as i n d u c t i o n of hepatic e n z y m e systems, w h i c h for drugs is an acceptable effect b u t for e n v i r o n m e n t a l pollutants is unacceptable. T h e m a i n thesis of this chapter is that v a l i d , w e l l - d o n e e p i d e m i o l o g i c a l studies of h u m a n s s h o u l d p l a y a v i t a l role i n risk assessment. R e l y i n g o n l y o n extrapolation f r o m a n i m a l studies may l e a d to seriously o v e r e s t i m a t i n g or u n d e r e s t i m a t i n g the risk. Regulations based o n overestimates c a n have serious, unnecessary econ o m i c consequences b o t h b y k e e p i n g e c o n o m i c a l l y desirable products from

This chapter not subject to U.S. copyright Published 1994 American Chemical Society

Draper; Environmental Epidemiology Advances in Chemistry; American Chemical Society: Washington, DC, 1994.

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ENVIRONMENTAL EPIDEMIOLOGY


b e i n g m a r k e t e d a n d u s e d a n d b y causing expensive c l e a n u p actions that have no benefit to h e a l t h . N e v e r t h e l e s s , a c o m p l e t e l y laissez-faire p o l i c y about these substances can b e disastrous; w e have o n l y to look to E a s t e r n E u r o p e a n d to some d e v e l o p i n g countries to see its devastating result. O v e r the past decade, scientists have e x p e n d e d m a n y m i l l i o n s of p u b l i c a n d p r i v a t e research dollars to investigate a n d u n d e r s t a n d the c o m p l e x r e lationships b e t w e e n h u m a n h e a l t h a n d exposure to e n v i r o n m e n t a l p o l l u tants. T h e basic tools o f this o n g o i n g search are laboratory studies i n animals, studies of m o l e c u l a r biology, a n d e p i d e m i o l o g i c a l studies of h u m a n s . P r o p e r l y d o n e , a n i m a l e x p e r i m e n t s a n d e p i d e m i o l o g i c a l studies p r o v i d e a basis for l i n k i n g various h u m a n h e a l t h risks a n d e n v i r o n m e n t a l factors; from these associations, p u b l i c h e a l t h a n d e n v i r o n m e n t a l p r o t e c t i o n policies can be d e v e l o p e d to m i n i m i z e the risks to c u r r e n t a n d future populations. H o w e v e r , information o b t a i n e d b y means of these t o o l s — a n i m a l toxicological studies a n d h u m a n e p i d e m i o l o g i c a l investigations—has often b e e n m i s a p p l i e d b e cause of the scientific c o m m u n i t y ' s failure to clarify the n a t u r e a n d l i m i t a tions o f o u r k n o w l e d g e about e n v i r o n m e n t - r e l a t e d h e a l t h risks. M o s t illnesses clearly caused b y chemicals are e n c o u n t e r e d as exposures i n occupational a n d nonoccupational settings. A n u m b e r of diseases are k n o w n to b e caused b y exposure to c e r t a i n c h e m i c a l or p h y s i c a l agents. S o m e diseases have no other k n o w n cause; these i n c l u d e asbestosis, r a d i a tion sickness, caisson disease (decompression illness), a n d m e s o t h e l i o m a , w h i c h is usually caused b y asbestos. I n the case of some other illnesses, the c h e m i c a l - d i s e a s e l i n k is strong b u t not u n i q u e . V i n y l c h l o r i d e causes a rare cancer of the liver, angiosarc o m a , b u t this o u t c o m e may also b e caused b y c e r t a i n arsenicals a n d a n d r o genic anabolic steroids. T h e s k i n disease chloracne is caused b y a n u m b e r o f halogenated aromatic h y d r o c a r b o n s , such as the c h l o r i n a t e d naphthalenes, c h l o r i n a t e d b i p h e n y l s , c h l o r i n a t e d d i b e n z o d i o x i n s , some c h l o r i n a t e d azobenzenes, a n d c h l o r i n a t e d dibenzofurans. F o r other diseases, i t is e v e n m o r e difficult to establish an actual cause. F o r instance, b e n z e n e has b e e n s h o w n to be associated w i t h a h i g h e r i n c i d e n c e of aplastic a n e m i a a n d myelogenous l e u k e m i a i n w o r k e r s w h o have b e e n exposed to h i g h concentrations of the solvent. Because b o t h aplastic a n e m i a a n d myelogenous l e u k e m i a are also r e l a t i v e l y p r e v a l e n t i n the g e n eral p o p u l a t i o n , it is difficult to d e t e r m i n e i n a n i n d i v i d u a l w h e t h e r the d i s ease was caused b y the specific agent of c o n c e r n o r b y some o t h e r u n k n o w n factor. I n a d d i t i o n to cancer, m a n y acute a n d c h r o n i c diseases w i t h p o t e n t i a l or p e r c e i v e d c h e m i c a l causes occur r e l a t i v e l y f r e q u e n t l y i n the general p o p u lation. T h e s e i n c l u d e heart disease a n d stroke i n c o n j u n c t i o n w i t h a r t e r i o sclerosis, diabetes, c h r o n i c obstructive l u n g disease, arthritis, a n d i m m u nological a n d n e u r o m u s c u l a r disorders. O t h e r concerns are for c o n g e n i t a l malformations a n d other u n t o w a r d outcomes of pregnancy. F u r t h e r m o r e , e m o t i o n a l p r o b l e m s , infertility, a n d psychological disorders a m o n g b o t h


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sexes are often r e p o r t e d b y p e o p l e w h o fear that t h e i r h e a l t h has b e e n d a m aged b y exposure to chemicals. F o r a l l of these conditions, it is r a r e l y possible to demonstrate c o n c l u s i v e l y a causal role for c h e m i c a l exposure. F o r these reasons, w e m u s t use some m e t h o d of c o m p a r i s o n , s u c h as relative risk for exposed a n d nonexposed populations, a n d w e m u s t b e s c r u pulous i n i d e n t i f y i n g a n d accounting for a l l p o t e n t i a l c o n f o u n d i n g factors. W e must also b e careful to define, quantify, a n d validate that exposure. W h e n exposure can be v a l i d a t e d w i t h laboratory measurements of b o d y b u r d e n , i n m a n y instances w e f i n d that u s i n g e n v i r o n m e n t a l data a n d q u e s t i o n naires results i n u p to 4 0 % misclassification—about the same as o b t a i n e d b y the toss of a c o i n . I f exposure cannot be v a l i d a t e d , w e must be careful i n i n t e r p r e t i n g the data, e v e n to the p o i n t of a d m i t t i n g that misclassification p r e c l u d e s v a l i d conclusions. I n quantitative risk assessment, investigators use the results of high-dose f e e d i n g studies a n d extrapolate the results to untested low-dose exposure levels i n the same species; t h e n they extrapolate these extrapolated findings across species to h u m a n s . T h e factors i n v o l v e d i n quantitative risk assessment are scientific fact, consensus, assumption, a n d science policy. B y science policy, I m e a n the agency's decision about h o w to h a n d l e controversial data. T h e most c e r t a i n factor, scientific fact, is usually the least available. W e have yet to d e t e r m i n e h o w far the others deviate f r o m the t r u t h . T h e degree of certainty appears to decrease as one reads t h r o u g h the list. I n " c h r o n i c " feeding studies of laboratory animals at the m a x i m u m t o l erated dose, m o r e than one-half of the tested chemicals have b e e n s h o w n to increase the i n c i d e n c e of tumors. A s a result, these chemicals have b e e n classified as a n i m a l carcinogens a n d , b y i m p l i c a t i o n , possible h u m a n c a r c i n ogens, e v e n t h o u g h (1) m a n y of t h e m have s h o w n little or no mutagenicity, a n d (2) evidence of h u m a n carcinogenesis is l a c k i n g . It does not seem to matter, for example, w h e t h e r the d e v e l o p m e n t of these tumors is relevant to h u m a n m e t a b o l i s m or e v e n w h e t h e r the tumors may occur i n organs or tissues not found i n h u m a n s . D u r i n g the 1970s, a m o d e l was d e v e l o p e d b y consensus for the c a r c i nogenicity of chemicals. It was based o n experience w i t h r a d i a t i o n , w h i c h defined a l i n e a r relationship b e t w e e n dose a n d response over a w i d e range of exposures. S t u d y results s h o w e d that i o n i z i n g radiation p r o d u c e d genetic mutations that l e d to t u m o r d e v e l o p m e n t i n exposed populations. T h e s e r a d i a t i o n - i n d u c e d mutations w e r e o b s e r v e d i n animals, plants, a n d bacteria. B y u s i n g bacteria, investigators c o u l d study the response c u r v e p r o d u c e d b y v e r y l o w doses. T h i s radiation experience of s e e m i n g l y u n e n d i n g c e l l u l a r response to ever-decreasing radiation doses stood i n stark contrast to a f u n d a m e n t a l r u l e of chemicals i n toxicology—that is, the dose makes the poison. T h u s , c o n sensus abrogated a l o n g - h e l d p r i n c i p l e of toxicology a n d , w i t h scant e v i d e n c e , d e t e r m i n e d that for c h e m i c a l l y i n d u c e d carcinogenesis, no exposure is free of threat.


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T h e radiation m o d e l for carcinogenicity was based o n the s i m p l e c o n c e p t that a l l cancer is caused b y m u t a t i o n of the c e l l u l a r D N A . Because results of a n i m a l studies h a d c o n f i r m e d a d o s e - r e s p o n s e r e l a t i o n s h i p for r a d i a t i o n a n d t u m o r d e v e l o p m e n t , l o n g - t e r m , high-dose bioassays b e c a m e the c h o i c e for s t u d y i n g the p o t e n t i a l carcinogenic effects of chemicals. A dose a p p r o a c h i n g the m a x i m u m tolerated dose was selected to ensure that n o p o s i t i v e response was m i s s e d a n d because the fewer animals n e e d e d to demonstrate a response meant a less expensive test. F o r the past 20 years, r o d e n t f e e d i n g has p l a y e d the l e a d i n g r o l e i n d e t e r m i n i n g the carcinogenicity of chemicals. R e g u l a t o r y science has largely lost sight of the basis of the radiation m o d e l that r e q u i r e d not o n l y a dosed e p e n d e n t response b u t , m o r e i m p o r t a n t , agent-caused genetic mutations. W e have b e e n d r i v e n b y the e n d p o i n t , cancer d e v e l o p m e n t , forgetting that w e m u s t also u n d e r s t a n d the means to the e n d . T h u s , a host o f chemicals have s h o w n an increased t u m o r i n c i d e n c e , c o m p a r e d w i t h controls. M o s t show little or n o m u t a g e n i c activity. O v e r the last two decades, the p u r p o s e of l i f e t i m e bioassays has shifted from investigating the m e c h a n i s m o f c a r c i n o g e n i c i t y to a c c u m u l a t i n g data f r o m w h i c h to calculate the supposed h u m a n cancer p o t e n t i a l of chemicals. M a n y scientists n o w u n d e r s t a n d that l o a d i n g an a n i m a l w i t h a c h e m i c a l for a l i f e t i m e for the purpose of c o u n t i n g t u m o r s i n o r d e r to satisfy a m a t h ematical extrapolation m o d e l , does not necessarily p r e d i c t its p o t e n t i a l for carcinogenicity i n h u m a n s . I n the early days o f risk assessment, this m o d e l i n g approach was the " o n l y game i n t o w n " . It c o m b i n e d some a n i m a l data, statistics, a n d m a t h e m a t i c a l extrapolation to evaluate w h i c h chemicals m a y p r o d u c e a specific h u m a n h e a l t h effect. T h i s c o m b i n a t i o n process, i n its m a n y forms, b e c a m e the basis of science policy. M o s t scientists n o w recognize that not a l l chemicals fit the radiation m o d e l of carcinogenesis. T h u s , for nongenotoxic chemicals, w e n e e d another approach that allows us to p r o p e r l y protect the p u b l i c s h e a l t h w i t h o u t wasti n g resources because of excessive r e g u l a t i o n , as may b e dictated b y the l i n e a r i z e d multistage extrapolation m o d e l . A l t h o u g h the results of a n i m a l studies m a y i m p l y carcinogenicity i n h u mans, the results of e p i d e m i o l o g i c a l studies have i d e n t i f i e d chemicals that have p r o v e d to be h u m a n carcinogens. F r o m the association of scrotal cancer i n c h i m n e y sweeps w i t h soot to l i v e r angiosarcoma of plant w o r k e r s w i t h v i n y l c h l o r i d e — t o n a m e o n l y two e x a m p l e s — e p i d e m i o l o g y has i d e n t i f i e d the r e l a t i o n s h i p . W e m u s t not d i s r e g a r d the results of h u m a n experience w h e n evaluating the i m p l i c a t i o n s of a n i m a l studies. T h e e v i d e n c e g a i n e d from h u m a n studies is s t r e n g t h e n e d b y consistency a m o n g several studies. C o n f l i c t i n g results a m o n g w e l l - d o n e , large e p i d e m i o l o g i c a l studies raise serious doubts about apparent associations. It becomes e v i d e n t that m a n y factors i n f l u e n c e the d e v e l o p m e n t of d i s ease. S o m e illnesses, i n c l u d i n g m a n y cancers, m a y have latency p e r i o d s of


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2 0 - 4 0 years. M o r e o v e r , i n general, e n v i r o n m e n t a l exposure to synthetic chemicals has b e e n at r e l a t i v e l y l o w concentrations a n d t h r o u g h a v a r i e t y of r o u t e s — i n h a l a t i o n , ingestion, a n d absorption t h r o u g h the s k i n . A s a result, it is n o w i m p o s s i b l e to d e t e r m i n e p r e c i s e l y for the i n d i v i d u a l the events that l e d to the d e v e l o p m e n t of disease. T h e state of the art i n m e d i c a l science or e p i d e m i o l o g y is not such that w e can p r e d i c t w i t h c e r t a i n t y w h e t h e r a p e r son w h o has b e e n exposed to chemicals w i l l u l t i m a t e l y d e v e l o p a p a r t i c u l a r disease or c o n d i t i o n . I n most cases, the c o n c l u s i o n must b e d r a w n that the scientific database n o w available does not p e r m i t a c e r t a i n d e t e r m i n a t i o n of w h e t h e r exposure has a causal r e l a t i o n to illness i n h u m a n s . T h e data n o w available do p r o v i d e sufficient e v i d e n c e to r e d u c e exposure, a n d thus possibly to p r e v e n t disease i n the future. T h e r e is a reason for this d i c h o t o m y b e t w e e n p r e v e n t i o n a n d a t t r i b u t i o n of cause. T h e studies that generate i n f o r m a t i o n about the c h r o n i c low-dose toxic effects of chemicals do not p e r m i t p r e d i c t i o n s w i t h f u l l c o n fidence about the h e a l t h of an i n d i v i d u a l , b u t they do assess the h e a l t h of a p o p u l a t i o n a n d what degree of risk a g i v e n p o p u l a t i o n w i l l r u n i f exposure continues. P r o p e r use of the scientific data can l e a d to major p u b l i c h e a l t h benefits; the application to that p u r p o s e is b o t h responsible a n d just. H o w e v e r , to press such data into service to e x p l a i n the cause of an i n d i v i d u a l s disease carries a great p o t e n t i a l for misuse of the data. E p i d e m i o l o g i c a l studies n e v e r p r o v e cause a n d effect, a l t h o u g h i n some instances, reasonable p e o p l e w o u l d accept t h e m as proof. It is not e t h i c a l to p u r p o s e l y expose i n d i v i d u a l s to hazardous substances. I n studies of h u m a n s , investigators m u s t f i n d o n l y instances of i n a d v e r t e n t exposure, a n d w e m u s t design studies that p r o v i d e the best-possible e v i d e n c e for or against an association. To assess risk optimally, w e m u s t gather a l l the d a t a — h u m a n a n d a n i m a l — a n d c o m b i n e t h e m w i t h the soundest professional j u d g m e n t . W e m u s t recognize that the multistage l i n e a r i z e d m o d e l for quantitative risk assessm e n t is not appropriate for a l l chemicals. A t the same t i m e , w e m u s t ack n o w l e d g e that the results of a p u b l i s h e d e p i d e m i o l o g i c a l study are not n e c essarily the final answer. M a n y of the e p i d e m i o l o g i c a l tools, unless u s e d i m p e c c a b l y w i t h large e n o u g h populations, w i l l y i e l d i n c o n c l u s i v e r e s u l t s — n e i t h e r positive n o r negative. O u r major l i m i t a t i o n is dose quantification, a p r o b l e m that is r e l a t i v e l y s i m p l e to solve for laboratory animals. I n e p i d e m i o l o g i c a l studies, i n v e s t i gators f r e q u e n t l y use qualitative indicators of dose, s u c h as " h i g h " , " m e d i u m " , a n d " l o w " or " y e s " a n d " n o " . A s stated, such studies have a significant p r o b l e m w i t h misclassification a m o n g the p o t e n t i a l l y exposed a n d u n e x p o s e d groups. To illustrate the n e e d to base p u b l i c h e a l t h j u d g m e n t o n a l l data c o m b i n e d , two examples are p r o v i d e d .


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Lead E a r l y o n , adverse consequences o f exposure to l e a d w e r e associated w i t h the w o r k p l a c e , affecting the w o r k e r s a n d t h e i r families a n d those i n the i m m e diate v i c i n i t y o f the w o r k p l a c e t h r o u g h e n v i r o n m e n t a l releases. O t h e r s have b e e n exposed t h r o u g h i n g e s t i n g m a t e r i a l that contains l e a d . T h e s e are p r i m a r i l y y o u n g c h i l d r e n w h o ingest p a i n t c h i p s a n d soil a n d dust that contains v e r y s m a l l particles o f l e a d . T h e w i d e s p r e a d use o f l e a d e d gasoline as an a u t o m o b i l e f u e l i n t r o d u c e d another source of l e a d , a n d i n h a l a t i o n b e c a m e a significant route o f exposure i n high-traffic areas, not j u s t i n t h e v i c i n i t y o f smelters. L a b o r a t o r y a n i m a l data for l e a d p r o v i d e d b o t h a lowest o b s e r v e d a d -


verse effect l e v e l ( L O A E L ) a n d a no o b s e r v e d adverse effect l e v e l ( N O A E L ) for exposure to l e a d . T h e s e early a n i m a l values w e r e , for some e n d p o i n t s , greater t h a n o r e q u a l to levels seen i n w o r k e r s a n d t h e i r c h i l d r e n . F o r c h i l d r e n i n the U n i t e d States before the m i d - 1 9 6 0 s , a l e v e l o f l e a d b e l o w 60 jJig/dL i n w h o l e b l o o d was not c o n s i d e r e d dangerous e n o u g h to r e q u i r e i n t e r v e n t i o n . S u b s e q u e n t research n o t e d adverse h e a l t h effects o n h u m a n s w i t h l o w e r b l o o d levels; i n 1985 the t h r e s h o l d was l o w e r e d to 25 f x g / d L , a n d m o r e r e c e n t l y to as l o w as 10 [xg/dL. Studies o f h u m a n s have since d e m o n s t r a t e d adverse effects at l o w e r b l o o d l e a d levels. Effects of i n utero exposure i n c l u d e decreased gestational age a n d b i r t h w e i g h t a n d r e t a r d e d m e n t a l d e v e l o p m e n t . T h e effects i n c h i l d r e n , for w h i c h no t h r e s h o l d has b e e n d e f i n e d , i n c l u d e d e c r e m e n t s i n I Q and hearing, diminished growth, and reduced vitamin D metabolism. F o r adults, t h e y i n c l u d e i n c r e a s e d b l o o d p r e s s u r e i n m e n . B e c a u s e o f the effects of low-dose exposure, the l e v e l o f b l o o d l e a d w a r r a n t i n g c o n c e r n i n t h e U n i t e d States has b e e n r e d u c e d to 10 j x g / d L . T h i s t h r e s h o l d was selected not because l o w e r levels are w i t h o u t c o n s e q u e n c e s , b u t because of a p r a c tical n e e d to r e d u c e the c u r r e n t b l o o d l e a d levels i n the g e n e r a l p o p u l a t i o n .

Dioxin F o r the class of c h e m i c a l s k n o w n as dioxins a n d furans a n d specifically for 2 , 3 , 7 , 8 - t e t r a c h l o r o d i b e n z o - p - d i o x i n , w e n o w have m o r e scientific facts t h a n for most chemicals. F o r m o r e t h a n a decade, t h e results o f a n i m a l studies have s h o w n d i o x i n to b e the most potent c a r c i n o g e n i c s y n t h e t i c c h e m i c a l tested. It has also b e e n said that it is " t h e most toxic m a n - m a d e c h e m i c a l k n o w n to m a n " . W e n o w recognize that most, i f not a l l , of the b i o l o g i c a l a n d toxic effects of d i o x i n are r e c e p t o r - m e d i a t e d . W e k n o w that i n animals each of these c e l l u l a r manifestations o f d i o x i n - r e c e p t o r - m e d i a t e d activity shows a c o n c e n t r a t i o n b e l o w w h i c h t h e r e is n o observable c e l l u l a r response. D i o x i n is not c o n s i d e r e d to b e genotoxic. I f its m o d e o f action for c a r cinogenesis is e i t h e r r e c e p t o r - m e d i a t e d o r t o x i c i t y - i n d u c e d c e l l p r o l i f e r a t i o n , the available scientific i n f o r m a t i o n indicates that the l i n e a r i z e d m u l t i -


1.

HOUK

Assessing Environmental

Risk

7

stage m o d e l is inappropriate for e s t i m a t i n g excess l i f e t i m e cancer risk to h u m a n s from the results of a n i m a l studies.


Before w e c o u l d measure d i o x i n i n h u m a n s , the most consistent p h y s i c a l m a r k e r of h i g h - l e v e l h u m a n exposure to d i o x i n was chloracne. M o r e than 450 cases of chloracne have b e e n r e c o r d e d i n w o r k e r s i n v o l v e d i n eight "acc i d e n t s " i n t r i c h l o r o p h e n o l plants that o c c u r r e d b e t w e e n 1949 a n d 1968 i n several countries a r o u n d the w o r l d . O t h e r cases have o c c u r r e d i n h u n d r e d s of w o r k e r s exposed to r o u t i n e leaks a n d spills. H e a v y exposures, usually s t e m m i n g from p r o d u c t i o n " a c c i d e n t s " that contaminate w o r k e r s w i t h (2,4,5trichlorophenoxy)acetic a c i d , d i o x i n , a n d other chemicals have b e e n related to transient neurological a n d l i v e r effects, w h i c h i n almost a l l cases d i s a p p e a r e d w i t h the passage of t i m e . O n e of the most h e a v i l y exposed populations i n the w o r l d is that a r o u n d Seveso, Italy. T h a t p o p u l a t i o n of about 30,000 i n d i v i d u a l s u n d e r study i n cludes about 700 w h o l i v e d i n or w h o w e r e i n the most c o n t a m i n a t e d area. W e have m e a s u r e d d i o x i n content o f u p to 56,000 parts p e r t r i l l i o n i n the l i p i d p o r t i o n of s e r u m i n some of those i n d i v i d u a l s or about 10,000 times the m e a n b a c k g r o u n d levels for the U . S . p o p u l a t i o n . C h l o r a c n e is the o n l y d i s ease yet found i n the Seveso p o p u l a t i o n . T h e m e a n dose to the Seveso c h i l d r e n w h o d e v e l o p e d chloracne, about 3 u,g/kg, is t h r e e times as h i g h as the dose of 1 |mg/kg that kills h a l f of the g u i n e a pigs exposed to i t . T h e r e c e n t l y c o m p l e t e d C e n t e r s for Disease C o n t r o l N a t i o n a l Institute for O c c u p a t i o n a l Safety a n d H e a l t h ( N I O S H ) study of cancer m o r t a l i t y i n w o r k e r s exposed to d i o x i n adds considerable b u t not conclusive e v i d e n c e about its relationship to cancer. E x p o s u r e i n this p o p u l a t i o n has b e e n v a l i dated b y laboratory measurements of dioxins. T h i s is a study of m o r e than 5000 p r o d u c t i o n workers i n the U . S . c h e m i c a l i n d u s t r y a n d is p r o b a b l y the largest a n d most elegant study that is possible. I n g e n e r a l , the study s h o w e d that over 1500 i n d i v i d u a l s w h o h a d the highest exposure (600 times background) h a d a modest increase of a l l cancers c o m b i n e d [standard m o r t a l i t y rate ( S M R ) = 146] a n d of cancers of the l a r y n x , b r o n c h u s , a n d l u n g ( S M R = 142). T h e r e w e r e no increases i n cancer i n the 1500 i n d i v i d u a l s w h o h a d b e e n exposed for less than 1 year b u t w h o s e s e r u m d i o x i n levels w e r e 60 times b a c k g r o u n d levels, a n d there was no increase i n the 2000 other i n d i v i d u a l s w h o h a d lesser exposures. I n a d d i t i o n , the c o n t r i b u t i o n of exposure to other chemicals c o n f o u n d i n g the results i n this N I O S H study c a n not b e fully evaluated. W i t h the exception of c h l o r a c n e — a p o t e n t i a l l y d i s f i g u r i n g b u t n o n - l i f e t h r e a t e n i n g s k i n c o n d i t i o n — t h e r e are no c o n v i n c i n g data that l i n k exposure of h u m a n s to d i o x i n , e v e n at v e r y h i g h levels, w i t h early mortality, adverse r e p r o d u c t i v e outcomes, or c h r o n i c diseases of the l i v e r o r the i m m u n e , cardiovascular, or n e u r o l o g i c a l systems. A l t h o u g h the q u e s t i o n of its l i n k w i t h cancer is not settled, i f d i o x i n is a h u m a n c a r c i n o g e n , I b e l i e v e it is a weak one that is associated o n l y w i t h v e r y - h i g h - d o s e exposures. F u r t h e r m o r e , I


8


b e l i e v e that d i o x i n , i f it is a h u m a n carcinogen, acts as a p r o m o t e r , not as a n initiator. T w o w e l l - d o n e studies i n w o r k e r s support the last two conclusions.

Conclusion


D i o x i n a n d lead are good examples of w h y w e m u s t use b o t h a n i m a l a n d h u m a n data to evaluate the p o t e n t i a l h e a l t h effects of c h e m i c a l exposure i n h u m a n s . T h e early a n i m a l studies o f l e a d s e e m e d to show n o effects at c o n centrations greater than those e x p e r i e n c e d b y h u m a n s f r o m m a n y e n v i r o n m e n t a l exposures. F u r t h e r investigations w i t h h u m a n s , however, have s h o w n several effects for w h i c h no t h r e s h o l d has b e e n d e f i n e d . T h u s , w e c o n t i n u e efforts to r e m o v e lead from use a n d to reduce its e n v i r o n m e n t a l release to the greatest extent possible. W e n o w have good i n f o r m a t i o n about d i o x i n s mechanisms of toxicity i n animals. T h e no-effect l e v e l for various toxicological effects i n animals is a daily dose of about 1 0 0 0 p g / k g . B y u s i n g k i n e t i c data, w e can equate this to a d a i l y dose of 1 0 0 p g / k g b o d y w e i g h t i n h u m a n s . W e also have good i n f o r m a t i o n o n the effects o n h u m a n h e a l t h u n d e r steady-state conditions. T h e s e data indicate that the e n v i r o n m e n t a l levels of d i o x i n to w h i c h the g e n e r a l p o p u l a t i o n is n o w exposed are not e n o u g h to warrant c o n c e r n for h u m a n health. W e do not want that exposure to increase, b u t n e i t h e r n e e d w e u n dertake expensive e n v i r o n m e n t a l c l e a n u p actions w h e r e the c o n t a m i n a t i o n has already o c c u r r e d . C o m b i n i n g a l l the data about h e a l t h risk for a p a r t i c u l a r substance m a y not p r o v i d e the conclusive answers that are so m u c h i n d e m a n d . N e v e r t h e less, w e b e l i e v e that w e can demonstrate strong associations, w h e r e t h e y exist, b e t w e e n exposure a n d adverse h e a l t h outcomes so that reasonable p e o p l e can take reasonable actions to protect p u b l i c h e a l t h a n d the e n v i r o n m e n t . T h u s , w e see the role of p u b l i c h e a l t h agencies as p r i m a r i l y one of p r e v e n t i o n — j u s t as it has always b e e n . R E C E I V E D for r e v i e w S e p t e m b e r 3 , 1 9 9 2 . A C C E P T E D r e v i s e d m a n u s c r i p t April 3,1993.


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