The Successes and Failures of Environmental ... - ACS Publications

17 The Successes and Failures of Environmental Epidemiology Raymond Richard Neutra

Downloaded by CORNELL UNIV on August 24, 2016 | http://pubs.acs.org Publication Date: May 5, 1994 | doi: 10.1021/ba-1994-0241.ch017

Environmental Health Investigations Branch, California Department of Health Services, 5900 Hollis Street, Suite E, Emeryville, C A 94608

Environmental

epidemiologists and analytical chemists

find themselves in a sort of intercultural

marriage.

increasingly

They make an

odd couple but an effective one. A review is presented on how the instincts and training of the two disciplines differ and why so much of the practice of environmental epidemiology may seem counterintuitive to a chemist. The successes of environmental epidemiology can come from discovering a hazard, its effective dose, or the environmental conditions that deliver it to susceptible populations.

Another

kind of success is showing that a particular dose and route of exposure do not seem to explain a disease outbreak. Examples of both kinds of successes are given, and the conditions that promise each are discussed. It is argued that despite the overreaction of the media to individual studies, epidemiology rarely leads to false-positive results in the regulatory process. However, epidemiology often fails to identify hazards, particularly

if they convey less than a 1.5-fold relative

risk.

CHEMISTRYISTHEQUINTESSENTIALEXPERIMENTALDISCIPLINE,w h e r e as e p i d e m i o l o g y o n l y observes the natural w o r l d a n d can c o n t r o l n o t h i n g . C h e m i s t s are reductionists w h o t r y to u n d e r s t a n d p h e n o m e n a i n the s i m plest terms i n systems that are isolated f r o m external influences. E p i d e miologists w a t c h the w o r l d as it is a n d accept the i n t e r p l a y of n u m e r o u s factors i n f l u e n c i n g p h e n o m e n a they are t r y i n g to study ( 1 ). C h e m i s t s can see subtle changes w i t h concentrations at the part p e r t r i l l i o n l e v e l , whereas epidemiologists can see o n l y the i n f l u e n c e of factors that cause a 1.5-fold o r h i g h e r change i n the diseases t h e y study. C h e m i s t s , because t h e y are experimentalists, are perfectionists a n d attempt to c o n t r o l a l l e x t e r n a l factors

0065-2393/94/0241-0245$08.00/0 © 1994 American Chemical Society

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

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ENVIRONMENTAL EPIDEMIOLOGY


to the greatest possible degree. E p i d e m i o l o g i s t s have no h o p e of c o n t r o l l i n g a n y t h i n g ; they s i m p l y must l e a r n to outsmart nature a n d to find c l e v e r ways to negotiate the i n h e r e n t messiness of the p r o b l e m s w i t h w h i c h t h e y are dealing. C h e m i s t s make the greatest effort to measure e v e r y t h i n g that is relevant to t h e i r e x p e r i m e n t s . E p i d e m i o l o g i s t s assume that m a n y u n m e a s u r e d factors are at w o r k a n d are satisfied w i t h s i m p l y b r a c k e t i n g the l i k e l y m a g n i t u d e of these u n s e e n effects. C h e m i s t s have t h e i r o w n t h e o r y a n d m e t h o d , whereas epidemiologists r e l y o n the t h e o r y of biology, use the statistical m e t h o d , a n d a p p l y the methods to a variety of disease p r o b l e m s as they arise. It is no w o n d e r that the c h e m i s t asks the e p i d e m i o l o g i s t , " H o w can y o u possibly use such an inexact n o n e x p e r i m e n t a l science that has so l i t t l e u n i q u e theory to d r i v e e n v i r o n m e n t a l policy, w h i c h is targeted to h e l p f u l chemicals that I synthesize or u s e ? " T h i s chapter discusses the successes a n d failures of e n v i r o n m e n t a l epidemiology, b e g i n n i n g w i t h the successes. W h a t do epidemiologists m e a n b y success? O n e k i n d of success is a " t r u e - p o s i t i v e " finding. I n this instance, a h u m a n h e a l t h risk is associated w i t h a c e r t a i n dose range of a c h e m i c a l r e c e i v e d b y way of an existing route of e n v i r o n m e n t a l exposure; epidemiologists, w i t h the h e l p of s u p p o r t i n g s c i entists, (1) detect that h a z a r d , (2) identify the dose that is hazardous, a n d (3) f i n d the exposure route b y w h i c h that k i n d of dose actually reaches p e o p l e . A n example of this w o u l d b e the events i n C a l i f o r n i a of J u l y 4, 1985. R e p o r t s of three i n d i v i d u a l s w h o d e v e l o p e d v o m i t i n g a n d d i a r r h e a w i t h i n h a l f an h o u r of eating a w a t e r m e l o n l e d to a f l u r r y of telephone calls to e m e r g e n c y rooms a r o u n d the state a n d to the realization that the pesticide aldicarb h a d b e e n i l l e g a l l y u s e d at a r a n c h g r o w i n g w a t e r m e l o n s . T h i s agent h a d t r a v e l e d u p the root of the w a t e r m e l o n into the fruit a n d a c h i e v e d a dose sufficient to p r o d u c e this illness. T h e h a z a r d was i d e n t i f i e d , the dose l e v e l was b r a c k e t e d w i t h the h e l p of analytical chemists, a n d , after serious detective w o r k , the route of exposure was d e t e r m i n e d . E a r l y detection of a d d i t i o n a l cases, b y means of calls to e m e r g e n c y rooms a r o u n d the state, l e d to p u b l i c w a r n ings a n d to the b a n of w a t e r m e l o n sales, w h i c h c u r t a i l e d what w o u l d have b e e n a w i d e s p r e a d e p i d e m i c of poisonings (2). A n o t h e r k i n d of success w o u l d b e the d e m o n s t r a t i o n of a " t r u e - n e g a t i v e " result. I n this case, no actual h u m a n h e a l t h risk from a c h e m i c a l i n a p a r t i c ular dosage a n d exposure route existed. E p i d e m i o l o g i s t s a n d s u p p o r t i n g s c i entists, after careful study, do not find any excess risk from that exposure and that dose. Epidemiologists do not provide generic exoneration of an agent, b e cause they always study the agent i n a particular real-life situation, w h i c h may not be relevant to another situation. A n e x a m p l e of a true-negative result w o u l d be o u r study of an episode of w e l l - w a t e r c o n t a m i n a t i o n w i t h t r i chlorethane ( T C A ) (3). W e s h o w e d that a c l u s t e r of miscarriages a n d b i r t h defects r e p o r t e d i n a n e i g h b o r h o o d near a l e a k i n g u n d e r g r o u n d tank c o u l d not b e caused b y that leak, because another n e i g h b o r h o o d w i t h m o r e c o n -


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tamination h a d not e x p e r i e n c e d an increased risk a n d because w i t h i n the " c l u s t e r " n e i g h b o r h o o d miscarriages a n d b i r t h defects h a d not o c c u r r e d at the homes u s i n g the most c o n t a m i n a t e d water (4). T h u s , T C A at close to 1 p p m i n water was not associated w i t h miscarriages or b i r t h defects. T h i s does not m e a n that T C A at h i g h e r doses w o u l d not pose a h a z a r d .


E p i d e m i o l o g y has w o r k e d successfully u n d e r the f o l l o w i n g four c o n d i tions: 1. W h e n a s u d d e n c h e m i c a l exposure i n w h i c h an illness is p r o d u c e d w i t h i n a v e r y short t i m e occurs, such as i n the clearly d o c u m e n t e d tragedy at B h o p a l i n I n d i a , w h e r e deaths a n d severe illness r e s u l t e d from a c h e m i c a l explosion (5). A n o t h e r example is the w a t e r m e l o n episode discussed earlier (2). 2. W h e n u n d e r t y p i c a l conditions a n d i n v e r y short periods of t i m e , a researcher can correlate a change i n a physiological function to the change i n an e n v i r o n m e n t a l pollutant. A n exa m p l e w o u l d be the study of asthmatic school c h i l d r e n at s u m m e r camps i n areas w h e r e it can be d o c u m e n t e d that as the air p o l l u t i o n from ozone fluctuates, b r o n c h o c o n s t r i c t i o n also fluctuates (6). 3 . W h e n an association has b e e n made b e t w e e n l o n g - t e r m exposures a n d l o n g - t e r m functional effects. T h e most famous exa m p l e is the demonstration that exposure to fairly l o w levels of l e a d , as j u d g e d from the a c c u m u l a t i o n of l e a d i n the t e e t h , is associated w i t h p o o r performance o n standard psychological tests (7). 4.

W h e n occupational studies have l i n k e d r e l a t i v e l y h i g h levels of c h e m i c a l exposure to the incidences of cancer i n w o r k e r s . T h e i r results have b e e n extrapolated d o w n w a r d to the l o w e r exposures i n the g e n e r a l e n v i r o n m e n t i n o r d e r to estimate the potential cancer risks f r o m e n v i r o n m e n t a l exposures. Usually, it is assumed that a l i n e a r dose relationship exists (8).

F o r extrapolation, w e assume that the rate ratio (i.e., the ratio of the rate of disease i n exposed a n d unexposed individuals) or the rate difference (i.e., the difference b e t w e e n rates i n exposed a n d unexposed individuals) increases l i n e a r l y w i t h doses. A t the h i g h e r dose levels, w e have actual o b servations and are i n t e r e s t e d i n k n o w i n g h o w that c u r v e w o u l d progress i f the dose w e r e to b e c o m e less a n d less a n d approach zero. C o m p l i c a t e d statistical models exist to do this, b u t they i n v o l v e a "leap of f a i t h " , d r a w i n g e i t h e r a straight l i n e or some c u r v i l i n e a r function f r o m the zone of actual observations d o w n to zero. Sometimes this has to be d o n e o n the basis of h u m a n evidence because no a n i m a l m o d e l for carcinogenesis is available;


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this has b e e n the case for arsenic a n d asbestos. I n other situations, w e have b o t h a n i m a l a n d h u m a n data. I n the case of c a d m i u m (9), it seems that h u m a n s are less sensitive than animals.


W h a t about failure? D o studies e v e r give a false-positive result, " c r y i n g w o l f " w h e n none is really l u r k i n g i n the v i c i n i t y ? Interestingly, there appears to b e no generally accepted example of a clearly unnecessary r e g u l a tion b e i n g i n s t i t u t e d o n the basis of faulty e p i d e m i o l o g i c a l studies. W h y is it difficult to find a clear-cut failure of the false-positive variety? T h e r e are a n u m b e r of reasons. Scientists are t r a i n e d to a v o i d false-positive results. T h i s is n e v e r clearly stated, b u t epidemiologists, as scientists, must recognize that t h e i r c r e d i b i l i t y w i t h i n society w i l l not s u r v i v e i f they c r y w o l f too often. T h i s is reflected i n the statistics epidemiologists use. T h e statistics g r e w out of some a d hoc decisions b y R o n a l d F i s h e r (10) i n the 1920s a n d are o n l y n o w b e g i n n i n g to receive c r i t i c a l réévaluation. T h e c o n v e n t i o n a l tests of statistical significance set t h e i r false-positive a n d false-negative errors (the a l p h a a n d beta errors) i n such a w a y as to a v o i d the false-positive ones. N o n e t h e l e s s , w e must acknowledge c o u n t e r v a i l i n g practices that c o u l d l e a d to false-positive results. T h e first is the examination of m a n y hypotheses that all have a chance to b e statistically significant. T h e second is the t e n d e n c y to p u b l i s h positive results. H o w e v e r , the regulatory process itself p r o v i d e s a m p l e opportunities for i n t e r e s t e d parties to challenge the e v i d e n c e u n d e r l y i n g any r e g u l a t i o n , a n d i n d u s t r y has the resources to h i r e scientists to subject any e p i d e m i o l o g i c a l study to the severest c r i t i c i s m . R e g u l a t i o n r e quires m o r e than one study to show a strong result. So regulation itself is u n l i k e l y to p r o d u c e a false-positive f i n d i n g . T h e same is not true for the m e d i a . T h e m e d i a do not refrain f r o m s e i z i n g the flimsiest e p i d e m i o l o g i c a l study to attract t h e i r readers a n d f r o m m a k i n g a story of it. T h e opposite failure is the e r r o r of the false-negative result, the " w o l f i n sheep's c l o t h i n g " . T h i s is an e r r o r that epidemiology, b y its v e r y n a t u r e , must make constantly, because the diseases s t u d i e d are rare, because a backg r o u n d rate is i n f l u e n c e d b y m a n y other factors, a n d because effects that may still be of social consequences are small. T h u s , b y s t u d y i n g a group that is too s m a l l , w e fail to see the effect of interest. E c o n o m i c constraints may also p r e v e n t us f r o m f o l l o w i n g an exposed g r o u p for a sufficient p e r i o d of t i m e , p a r t i c u l a r l y for diseases l i k e cancer, w h i c h has an i n c u b a t i o n p e r i o d that may b e as l o n g as 40 years. E p i d e m i o l o g i s t s also make the e r r o r of a false-negative finding because of t h e i r reluctance to study controversial t o p ics that defy c o n v e n t i o n a l k n o w l e d g e . C u r r e n t examples are electromagnetic fields a n d t h e i r p o t e n t i a l h e a l t h effects a n d the controversial assertion that some i n d i v i d u a l s suffer m u l t i p l e c h e m i c a l sensitivities to v e r y l o w levels of chemicals. I f w e do not study these p r o b l e m s , w e can n e v e r resolve t h e m one w a y o r the other. E p i d e m i o l o g i s t s may fail to detect an existing p r o b l e m w h e n they exa m i n e a c o m p l e x m i x t u r e i n w h i c h some u n i d e n t i f i e d c o m p o n e n t may b e


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hazardous. O n e classic example is the p r o b l e m of the " s i c k b u i l d i n g s y n d r o m e " or i n d o o r air p o l l u t i o n . E v i d e n c e exists that w o r k e r s i n b u i l d i n g s that use artificial v e n t i l a t i o n are m o r e l i k e l y to have episodes of i l l - d e f i n e d a n d bothersome symptoms a m o n g w o r k e r s ; yet e v e r y conceivable c h e m i c a l a n d m i c r o o r g a n i s m i n the v e n t i l a t i o n system has b e e n m e a s u r e d a n d no off e n d i n g c u l p r i t has b e e n i d e n t i f i e d . W e seem to b e l o o k i n g h e r e for a n e e d l e i n a haystack a n d cannot f i n d i t . T h e great t e m p t a t i o n is to l a b e l the w o r k e r s w i t h symptoms as s i m p l y h a v i n g a psychosomatic p r o b l e m , because w e have not found a measurable causal factor i n t h e i r b u i l d i n g . E p i d e m i o l o g i s t s can ascertain that s o m e t h i n g is h a p p e n i n g , b u t t h e y n e e d t h e i r colleagues i n the laboratory to h e l p f i n d that n e e d l e . F i n a l l y , just because an e p i d e m i o l o g i s t cannot i m p l i c a t e a cause, does not m e a n it is u n i m p o r t a n t . E p i d e m i o l o g i s t s t e n d to assume that an e n v i r o n m e n t a l p r o b l e m does not exist because an e p i d e m i o l o g i c a l study has failed to demonstrate it. A good example of this was the controversy surr o u n d i n g saccharin use i n the late 1970s. S o m e p r e l i m i n a r y e p i d e m i o l o g i c a l studies (11) h a d shown an association b e t w e e n b l a d d e r cancer a n d the use of saccharin i n soft d r i n k s . A n a n i m a l study h a d s h o w n that animals fed h i g h doses of saccharin d e v e l o p e d b l a d d e r cancer. F i n a l l y , an enormous casec o n t r o l study was c o n d u c t e d n a t i o n w i d e (12) a n d d i d not show a n association b e t w e e n saccharin a n d b l a d d e r cancer. S o m e epidemiologists i n t e r p r e t e d this f i n d i n g to m e a n that rats d e v e l o p b l a d d e r cancer f r o m saccharin b u t h u m a n s do not. I n fact, b y u s i n g the a n i m a l data to extrapolate to the h u m a n doses, a relative risk of o n l y 1.01 w o u l d have b e e n expected o n the basis of the usual saccharin dose i n diet d r i n k s . T h e study itself, a l t h o u g h e n o r m o u s , o n l y h a d the ability to detect a relative risk of 1.1 a n d c b u l d not have d e tected an effect as s m a l l as 1.01. N o w , it m i g h t b e said that i f it c o u l d o n l y cause a relative risk of 1.01, that is, a 1% excess i n the i n c i d e n c e of b l a d d e r cancer, a n d that this effect w o u l d be n e g l i g i b l e ; i n fact, that 1% w o u l d r e p resent about 800 cases of b l a d d e r cancer p e r year i n the U n i t e d States. Y o u can i m a g i n e w h a t trial lawyers w o u l d have d o n e i f they c o u l d have p r o v e n that a specific diet soda was actually p r o d u c i n g 800 cases of cancer a year. So, a l t h o u g h this is an excess of social interest, it is an excess that e p i d e miologists s i m p l y w i l l n e v e r b e able to see, e v e n i f it d i d exist.

Summary T h i s chapter r e v i e w e d some of the differences b e t w e e n c h e m i s t r y a n d e p i d e m i o l o g y a n d the successes a n d failures o f e n v i r o n m e n t a l epidemiology. E p i d e m i o l o g y has b e e n most successful w h e n focused o n large acute h e a l t h effects a n d has often b e e n a i d e d w h e n chemists have p r o v i d e d ways to assess levels of h a r m f u l chemicals i n the e n v i r o n m e n t or i n h u m a n tissues. It is less successful w h e n an agent causes a less than 5 0 % increase of disease i n c i d e n c e a n d w h e n the i n t e r v a l b e t w e e n the t i m e of exposure a n d the onset



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of disease is l o n g . E p i d e m i o l o g y is a u s e f u l i n s t r u m e n t that has d e f i n i t e l i m itations. T h e art is i n u s i n g this i n s t r u m e n t a p p r o p r i a t e l y . P e o p l e do not l o o k d o w n o n the sledge h a m m e r — t h e y j u s t d o n ' t use

it to e l i c i t k n e e - j e r k r e

flexes.


References

RECEIVED 11, 1993.

1. Kleinbaum, D. G.; Kupper, K. L.; Morgenstein H. Epidemiological Research; Van Norstrand Reinhold: New York, 1982. 2. Goldman, L. R.; Smith, D. F.; Neutra, R. R.; et al. Arch. Environ. Health 1990, 45, 229-236. 3. Wrensch, M.; Swan, S. H.; Lipscomb, J.; Epstein, D.; Fenster, L.; Claxton, K.; Murphy, P. J.; Neutra, R. R. Am. J. Epidemiol. 1990, 131, 283-300. 4. Wrensch, M.; Swan, S. H.; Murphy, P. J.; Lipscomb, J.; Claxton, K.; Epstein, D.; Neutra, R. R. Arch. Environ. Health 1990; 45, 210-216. 5. Andersson, N.; Muir, Κ. M.; Salmon, A. G.; Wells, C. J.; Brown, R. J.; Prunell, C. J.; Mittal, P. C.; Mehra, V. Lancet 1985, i, 751-762. 6. Lippman, M. J. Air Pollut. Control Assoc. 1989, 39, 672-695. 7. Mushak, P.; Davis, J. M.; Crocetti, Α.; et al. Environ. Res. 1989, 50, 11-36. 8. Hertz-Picciotto, I.; Gravitz, N.; Neutra, R. R. Risk Anal. 1988; 8, 205-214. 9. Collins, J.; Brown, J. P.; Painter, P. R.; Jamall, I. S.; Zeise, L. Α.; Alexeeff, G. V.; Wade, M.J.; Siegel, D. M.; Wong, J. J. Regulat. Toxicol. Pharmacol. 1992, 16, 57-72. 10. Fisher, R. A. The Design of Experiments; London, Oliver and Boyd; Edinburgh, United Kingdom, 1935. 11. Office of Technology Assessment. "Cancer Testing Technology and Saccharin"; Office of Technology Assessment: Washington, D C , October 1977. 12. Hoover, R. N.; Strasser, P. Lancet 1980, 837-840. for

review

September

3,

1992.

ACCEPTED

revised

manuscript


February

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