NOT FOR QUOTATION WITHOUT THE PERMISSION OF THE AUTHORS
Influence of Demographic Patterns on Human Response to Ekposure to Environmental Contamsinants: Heterogeneity Factors
A n a t o l i I. Ynshin A l a n J. B e m t e i n J a m e s W. V a u p e l
October 1985 WP-85-64
W o r k i n g P a p e r s a r e interim r e p o r t s on work of t h e international Institute f o r Applied Systems Analysis and have received only limited review. Views o r opinions expressed herein d o not necessarily r e p r e s e n t those of t h e Institute o r of its National Member Organizations.
INTERNATIONAL INSTITUTE FOR APPLIED SYSTEMS ANALYSIS 2361 Laxenburg, Austria
Influence of Demographic Patterns on Human Response to Errposure to Environmental
Contaminants: Heterogeneity Factors
Anatoli I. Yashin. Alan J. Bernstein and James W. Vaupel
1. INTRODUCTION
Reid Smith is a cigarette-smoking N e w Yorker. Taylor Smith is a r e t i r e d non- smoker who worked in a n asbestos factory f o r 35 y e a r s . Jamie Smith is a pregnant housewife from a small Southern town in t h e U.S. C a r t e r Smith is a f a r m e r who consumes inadequate levels of vitamin A, vitamin E, and magnesium in his daily diet.
Despite obvious similarities in surname and nationality and, perhaps, various o t h e r similarities, t h e responses of these f o u r people t o exposure t o identical amounts of environmental pollutants probably vary greatly.
A s a c i g a r e t t e smoker, Reid faces elevated r i s k s of a variety of diseases in- cluding lung c a n c e r and cardiovascular illness. He is probably sensitive t o cadmi- um, hydrocarbons, lead, nickel, and radioactive compounds. A s a n urban dweller, h e runs a g r e a t e r r i s k of developing r e s p i r a t o r y illnesses and is subsequently more susceptible t o a variety of r e s p i r a t o r y irritants.
Taylor, because of his lifetime avoidance of cigarettes, r u n s only a minimal risk from his long-term asbestos exposure. However, because a g e has weakened his immune and enzyme systems, h e is very possibly hypersusceptible t o pesticides, PCBs, and r e s p i r a t o r y i r r i t a n t s . Changes in his bone s t r u c t u r e have also probably increased his body's retention of flouride and thus made him more at r i s k t o heavi- ly f louridated water.
Jamie's pregnancy has increased h e r susceptibility t o carbon monoxide, in- secticides, cadmium, manganese, and lead, especially if s h e is not taking iron o r calcium supplements. Smoking would p r e s e n t high r i s k s both f o r herself and h e r fetus. In addition s h e very well may b e absorbing unusually high levels of carbon monoxide and nitrous oxide in h e r kitchen.
Finally, Carter's deficiencies of vitamin A, vitamin E, and magnesium, make him a high r i s k f o r exposure t o DDT, hydrocarbon carcinogens. PCBs, lead, ozone, and flouride. If he suffers from G-6-PD deficiency, a r e d blood cell disorder, his concurrent vitamin E deficiency probably makes him extremely sensitive t o erythrocyte oxidant s t r e s s and t o hemolytic precipitators such a s ozone.
It is generally accepted t h a t t h e risk of disease and death vary markedly by age and sex. However, t h e r e a r e also inherited and acquired factors t h a t cause vast differences in human susceptibility t o many pollutant exposures. Most people a r e less familiar with this wide range of heterogeneity precipitated by genetic make-up, life style, occupation, nutrition, residence location, etc.
The combined role of these many heterogeneity factors is often underestimat- ed. Y e t they a r e t h e major factors that determine t h e evolution of mortality and morbidity patterns within a population.
In this paper, w e examine a variety of heterogeneities present in environmen- tal pollutant susceptibilities, briefly look a t how attempts t o recognize hetero- geneity have played a role in efforts t o regulate pollutants, consider how likely shifts in t h e composition of population may affect morbidity and mortality r a t e s af- fected by environmental pollution, discuss how indirect heterogeneity factors can lead t o additional complications in interpretations of pollution-related mortality statistics, and offer several suggestive models of heterogeneous susceptibility.
2. DIFFERENT AGE GROUPS IN THE POPULATION HAVE DIFFERENT SUSCEP- TIBILITIES TO ENVIRONMENTAL POLLUTANTS
Age is one of t h e primary causes of differential susceptibility. Particularly f o r the very young and t h e very elderly, t h e r e exist a variety of significant dangers which may pose little o r no t h r e a t t o those in o t h e r life stages.
Infants' and children's immature immune systems and immature enzyme detoxif- ication systems reduce t h e i r body's ability t o rid itself of environmental pollutants (Calabrese 1978). Many pollutants t h a t have minimal effects on healthy adults, can, in children, accumulate in t h e body relatively unimpeded. (This helps explain why PCB, often present in high levels in mother's milk, is particularly dangerous t o breast-fed infants
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a t t h e precise time when they a r e least able t o process this dangerous environmental pollutant, their diet contains higher levels of PCB than the diet of any o t h e r age group.)Children up t o approximately a g e t e n a l s o s u f f e r from a deficiency of Immuno- globin A (IgA). This i s t h e primary immunoglobulin in t e a r s , saliva, nasal, bronchi- a l , and gastrointestinal s e c r e t i o n s (Eisen 1974; Koistinen 1975). IgA deficiency is widely believed to b e a s t r o n g contributing f a c t o r in u p p e r and lower r e s p i r a t o r y infections. Confirming t h i s hypothesis are studies showing t h a t children who live in more heavily polluted areas have been found to s u f f e r h i g h e r rates of r e s p i r a - t o r y infections t h a n t h o s e living in areas with fewer r e s p i r a t o r y i r r i t a n t s (Fos- burgh 1974).
Newborns up t o t h r e e months a l s o have l o w levels of enzyme superoxide dismu- tase (SOD), generally a r o u n d 65-80 p e r c e n t of adult levels (Ueda and Ogata 1978;
Rotilio et al. 1977; Legge et al. 1977). Enzyme SOD is one of t h e body's chief pro- tection mechanisms against high concentration dioxides, radiation, ozone, nitrogen dioxide, and p a r a q u a t . I n f e r i o r levels of enzyme SOD leave infants at highly elevat- e d r i s k s t o t h e toxicity of t h e s e environmental agents.
Common nutritional deficiencies also leave children hypersusceptible t o a v a r i e t y of environmental pollutants. Ninety-eight p e r c e n t of children between a g e s 2 and 3 r e c e i v e less t h a n t h e recommended daily allowance (RDA) of iron. This i s believed t o i n c r e a s e t h e i r r i s k of r e a c t i o n t o hydrocarbon carcinogens, lead, and manganese. sixty-five p e r c e n t of children between t h e s e a g e s a l s o r e c e i v e less t h a n t h e i r RDA of calcium, increasing t h e i r susceptibility to lead. The 10-30 p e r - c e n t of infants and c h i l d r e n who r e c e i v e sub-RDA levels of vitamin C have elevated susceptibilities to a r s e n i c , cadmium, c a r b o n monoxide, chromium, DDT, dieldrin, lead, mercury, n i t r i t e s , and ozone. And t h e 2 5 p e r c e n t of children a g e s 7 t o 1 2 who have sub-RDA levels of vitamin A in t h e i r d i e t are at i n c r e a s e d r i s k t o DDT, hydro- c a r b o n carcinogens, and PCBs.
Certain unique susceptibilities e x i s t f o r women in t h e i r child-bearing y e a r s . Oral c o n t r a c e p t i v e use, when combined with c i g a r e t t e consumption, poses a p a r t i c - u l a r t h r e a t . Among women u n d e r 50 y e a r s of a g e who smoked 35 or m o r e c i g a r e t t e s a day and used o r a l c o n t r a c e p t i v e s , t h e rate of myocardial infarction w a s estimat- e d to b e 20 times h i g h e r t h a n among those who had n e v e r smoked.
In G r e a t Britain between 1958 and 1971, t h e d e a t h rate f o r women aged 35-44 increased by o v e r a t h i r d . During t h i s time, c i g a r e t t e consumption by women in t h e a g e group i n c r e a s e d by 3 5 p e r c e n t and contraceptive pills came into popular use.
Another set of i n c r e a s e d r i s k s f a c e t h e aged. Like children, t h e elderly a l s o s u f f e r from relatively ineffective immune and enzyme systems, and s u f f e r in- c r e a s e d susceptibilities to many of t h e same environmental pollutants as t h e v e r y young (Calabrese 1978).
3. PEOPLE DIFFER
IN
THEIR BIOLOGICALLY STKPULATED SUSCEPTIBILITIES TO ENVIRONMENTAL CONTAMINANTSA v a r i e t y of pre-existing health conditions also produce s e v e r a l additional heterogeneities in susceptibility t o environmental pollutants. Individuals with asthma a r e unusually susceptible t o r e s p i r a t o r y i r r i t a n t s such as nitrogen dioxide, ozone, sulfates, and sulfur dioxide. People with cystic fibrosis are also at high r i s k from ozone and o t h e r r e s p i r a t o r y i r r i t a n t s . Diabetics a r e much more likely t o have negative r e a c t i o n s t o l a r g e , single doses of radiation. Sickle cell anemics r u n g r e a t e r r i s k s from e x p o s u r e t o aromatic amino and n i t r o compounds, c a r b o n monoxide, and cyanide.
Other less a p p a r e n t , largely genetic health f a c t o r s a r e a l s o believed t o play a major r o l e in t h e g r e a t v a r i e t y t h a t e x i s t s in individual susceptibility t o pollutants.
Rates of a r y l hydrocarbon hydroxylase (AHH) inducibility, a genetically controlled f a c t o r , a r e thought t o b e a key indicator of lung c a n c e r susceptibility. I t i s thought t h a t most chemical carcinogens must b e metabolically converted into t h e i r carcinogenic form, and h i g h e r levels of AHH inducibility have been connected with significantly elevated lung c a n c e r rates (Calabrese 1978).
The population frequencies of AHH inducibility have been determined. Among t h e United S t a t e s ' white population t h r e e distinct groups have been categorized:
low (53 p e r c e n t ) , intermediate (37 p e r c e n t ) , and high (10 p e r c e n t ) inducers (Kel- lermann et al. 1973). Kellermann's studies of bronchogenic carcinoma patients r e - vealed t h a t t h e intermediate and high AHH inducibility c o h o r t s had, respectively, 1 6 and 36 times g r e a t e r r i s k of lung c a n c e r than t h e low AHH inducibility group.
P a r t i c u l a r l y suggestive from a policy viewpoint are Kellermann's findings of strong positive c o r r e l a t i o n s between smoking, high inducibility and high rates of lung c a n c e r , and also between smoking, low inducibility and relatively low rates of lung c a n c e r . This o f f e r s a n intriguing insight into why i t i s possible f o r some heavy smokers t o n e v e r develop any signs of lung c a n c e r , while relatively light smokers may succumb t o lung c a n c e r at a n e a r l y age. Since AHH inducibility c a n b e t e s t e d f o r , i t may b e advisable t o s e t up screening clinics f o r smokers (as well as those considering s t a r t i n g smoking) t o give them a g r e a t e r insight into t h e r i s k s t o which they may b e subjecting themselves.
Another human genetic d i s o r d e r , glucose-6-phosphate dehydrogenase (G-6- PD) deficiency, may b e a key causal f a c t o r in t h e high susceptibility some individu- als have t o hemolytic stress conditions. G-6-PD i s a r e d blood cell enzyme needed t o maintain e r y t h r o c y t e membrane integrity. G-6-PD deficiency in male s u b j e c t s is
revealed by sensitivity t o primaquine. Approximately 11 p e r c e n t of American Black Males s u f f e r from G-6-PD deficiency (Beutler 1972), as d o 11 p e r c e n t of Mediter- r a n e a n Jews, 1 2 p e r c e n t of Filipinos, and 2-5 p e r c e n t of Chinese (Stokinger and Mountain 1963; Lazarow 1954).
Under hemolytic stress conditions such as e x p o s u r e t o most anti-malarial d r u g s , many industrial chemicals, some pre-existing o r g a n i c diseases, and a variety of o t h e r environmental e x p o s u r e s , G-6-PD deficients may develop hemolyt- i c anemia and b e unusually sensitive t o lead toxicity. I t may b e useful, although politically sensitive considering t h e distinct r a c i a l component of t h e disease, t o s c r e e n f o r G-6-PD deficiency among t h o s e who work extensively with a v a r i e t y of common chemicals.
Thalassemia i s a n o t h e r genetic r e d blood cell d i s o r d e r which may p r o d u c e heterogeneous susceptibility, a n abnormality in t h e rate of hemoglobin synthesis.
Thalassemia i s especially f r e q u e n t among people living in t h e Mediterranean re- gion, t h e Middle E a s t , and t h e Orient (Silvestroni and Bianco 1959).
A s screening for thalassemia h a s only o c c u r r e d infrequently t h e r e are f e w r e p o r t s relating i t s o c c u r r e n c e with pollutant r e a c t i o n s . However, i t is suspected t h a t thalassemia a g g r a v a t e s lead (Toche et al. 1960; Jonderko 1961) and benzene toxicity (Saita and Moreo 1959).
A final area of biological susceptibilities, intriguing in t h e i r universality are Circadian rhythms, t h e twenty-four h o u r cycles which o c c u r in cell growth, mi- tosis, hormonal levels, body t e m p e r a t u r e , and a v a r i e t y of o t h e r human functions.
These rhythms are suspected of playing an important r o l e in heterogeneous sus- ceptibility (Luce 1970; Halberg 1960).
If all people h a v e c e r t a i n p e r i o d s of t h e day during which t h e y s u f f e r in- c r e a s e d susceptibility, t h e n w o r k e r s who are employed in switch shift occupations (medicine, police, f i r e , industry) are being r e g u l a r l y f o r c e d into high r i s k situa- tions. Additional studies h a v e shown t h a t s o m e individuals are n e v e r a b l e t o com- pletely adjust t h e i r Circadian rhythms t o t h e i r work h a b i t s (Felton and P a t t e r s o n 1971; Teleky 1943). I t would s e e m d e s i r a b l e f o r t h e s e people t o avoid work s h i f t s falling in t h e i r high susceptibility periods.
4.
MANY
HETEROGENELTY FACTORS ARE ACQUIREDAnother important a r e a of c o h o r t susceptibilities involves those f a c t o r s not inborn, but acquired by selected lifestyle.
Among t h e s e f a c t o r s , t h e most important i s smoking. Cigarette consumption i s almost certainly t h e g r e a t e s t controllable f a c t o r in lung c a n c e r susceptibility. I t also a f f e c t s r i s k levels f o r a v a r i e t y of o t h e r diseases such as bronchitis, em- physema, and c a r d i o v a s c u l a r illness. In addition t o making i t s own contribution t o mortality and morbidity rates, smoking, when combined with a v a r i e t y of o t h e r fac- t o r s , can e x e r t a substantial influence on r i s k s from e x p o s u r e t o environmental pollutants. Numerous studies have led t o t h e conclusion t h a t t h e e f f e c t s of smoking and environmental a i r pollution, when both are p r e s e n t , cause more t h a n a n addi- tive i n c r e a s e in susceptibility (Stern 1977).
Cigarettes are also a major p r o d u c e r of c a r b o n monoxide. A f r e q u e n t CO ex- posure level f o r community a i r pollution i s 10-30 p a r t s p e r million (ppm) (11-33 mg/m3), o v e r 4-8 hours. In c o n t r a s t , five minutes of f r e q u e n t repetition smoking, considered t o b e a r e p r e s e n t a t i v e dose, will cause a n e x p o s u r e level of 400 ppm (440 mg/m3) (Stern 1977).
A high positive c o r r e l a t i o n h a s been found between smoking, increased pollu- tion levels, and incidence of bronchitis. Tellingly, high a i r pollution levels have been found t o have little e f f e c t on incidences of s e r i o u s bronchitis among non- smokers (Stern 1977).
Smoking may significantly a f f e c t diabetics. T h e r e i s r e s e a r c h indicating a sig- nif icant relationship, p a r t i c u l a r l y f o r male diabetics, between smoking p a t t e r n s and incidence of diabetic nephropathy, t h e most f r e q u e n t cause of d e a t h in young diabetics (Christiansen and Nerup 1978). Smoking i s believed t o i n c r e a s e a diabet- ics need f o r insulin and t o significantly i n c r e a s e t h e r i s k of glomerulosclerosis and retinopathy (West et al. 1980).
Smoking c a n a l s o c a u s e t h e development of vitamin C deficiency. Nicotine h a s been found t o significantly r e d u c e t h e a s c o r b i c acid content of human blood. Thus both smokers as well as infants who a r e b r e a s t f e d by mothers who smoke r u n elevated r i s k s of vitamin C deficiency r e l a t e d susceptibilities (McCormick 1952;
Andrze jewski 1966).
The a g e a smoker develops his habit i s negatively c o r r e l a t e d t o t h e r i s k s t h e smoker faces. The IV World Congress on Smoking and Health, held in Stockholm, concluded t h a t t h e younger a person is when h e starts t o smoke, t h e higher t h e
r i s k of disease. Lung c a n c e r rates of men in t h e i r fifties who began smoking when they were t h i r t e e n are 40 p e r c e n t g r e a t e r t h a n rates f o r men who began smoking at a g e 17. Continuing t h i s t r e n d , a man who began to smoke at a g e 27 h a s only 20 p e r c e n t t h e probability of developing lung c a n c e r of a man who began at a g e 17.
The d a n g e r s of smoking are not exclusively limited to t h e smoker. Maternal smoking during pregnancy h a s been determined to r e t a r d f e t a l growth. The a v e r - a g e weight of smoking mother's newborns is 200 grams less t h a n t h a t of offspring of non-smoking mothers. Follow-up studies of infants b o r n to smoking mothers have shown some continuing effects through a g e 7. Following a n examination of 12,000 patients, Murphy found t h a t smoking mothers are more likely to h a v e spontaneous a b o r t i o n s , p r e m a t u r e deliveries, and pre-natal loss t h a n non-smoking mothers.
An infant's susceptibility t o bronchitis o r pneumonia in t h e f i r s t y e a r of life i s doubled if t h e child's p a r e n t s smoke. Wheezing up to a g e five i s a l s o m o r e common.
Inadequate nutrition i n c r e a s e s pollutant susceptibility f o r a n extremely l a r g e segment of t h e population. Adequate nutrition may b e one of t h e b e s t ways to de- crease individuals' r i s k s t o a wide v a r i e t y of environmental pollutants. F o r in- s t a n c e , a n inadequate d i e t a r y level of vitamin E c a n significantly heighten a G-6- PD deficients susceptibility t o e r y t h r o c y t e oxidant stress (Calabrese 1984).
Nutrition deficiencies, caused by a v a r i e t y of factors including heterogeneous nutritional needs, are p a r t i c u l a r l y p r e v a l e n t among lower-income groups. In t h e U.S., roughly a q u a r t e r or m o r e of t h i s c o h o r t s u f f e r s from deficiencies of vitamin A and vitamin C, leading to elevated susceptibilities to h y d r o c a r b o n carcinogens, DDT, PCB, a r s e n i c , cadmium, c a r b o n monoxide, chromium, dieldrin, lead, mercury, n i t r i t e s , and ozone (Calabrese 1978,1980). In a n interesting c i r c u l a r r e s p o n s e , ex- posure t o PCBs, DDT, a n d dieldrin c a n e x a c e r b a t e vitamin A deficiency. A s t r o n g negative c o r r e l a t i o n h a s been found f o r vitamin A levels and lung c a n c e r r a t e s , even with matched smoking p a t t e r n s .
Other nutritional deficiencies c u t across poverty lines. F o r instance m o s t U.S.
m a l e s have a p a r t i a l magnesium deficiency which leaves them at i n c r e a s e d r i s k to flouride; people with kidney diseases often h a v e inadequate phosphorus levels and are susceptible t o lead toxicity; many women and s o m e men ingest less t h a n t w o - t h i r d s of t h e RDA f o r riboflavin and r i s k g r e a t e r harm f r o m e x p o s u r e to hydrocar- bon carcinogens, l e a d , a n d ozone.
Pregnancy i s a n o t h e r important pollutant r i s k c o r r e l a t i v e . The numerous phy- siological changes in a woman's body during pregnancy, i n c r e a s e t h e r i s k s posed t o h e r from a v a r i e t y of environmental pollutants. Some of t h e biggest changes a f f e c t nutritional requirements, particularly f o r calcium and iron. R e s e a r c h e r s have re- p o r t e d anemia in 1 5 t o 58 p e r c e n t of pregnant women (de Leeuw et al 1966). These deficiencies would consequently make pregnant women hypersusceptible t o t h e tox- ic e f f e c t s of manganese, cadmium, and lead.
Endogenous CO production c a n i n c r e a s e dramatically during pregnancy (Hunt 1975). Given a l r e a d y high body levels of c a r b o n monoxide, p r e g n a n t women a r e at heightened risk from e x p o s u r e t o environmental and smoking CO.
P r e g n a n t women h a v e a l s o been shown t o b e at g r e a t e r r i s k t o e x p o s u r e t o DDT and o t h e r insecticides. DDT-exposed workers have significantly h i g h e r levels of childbearing disruptions such as spontaneous miscarriage, pregnancy toxicosis, and p r e m a t u r e bursting of t h e amniotic s a c (Veis 1970).
Occupation-related susceptibility e f f e c t s do not only f a c e pregnant workers.
Radon-exposed uranium miners have been found t o have elevated levels of lung c a n c e r , and when smoking habits a r e taken into account, t h e positive c o r r e l a t i o n between radon e x p o s u r e and smoking a p p e a r s t o produce a multiplicative, r a t h e r t h a n additive e f f e c t ( S t e r n 1977). Similarly, coal workers who do smoke have sig- nificantly h i g h e r incidences of emphysema and h e a r t disease when compared with non-smoking coal w o r k e r s (Calabrese 1978).
The most extensive occupation-heterogeneity r e s e a r c h h a s been done f o r asbestos-exposed workers. A s far back as t h e 1920s, W.E. Cooke in t h e B r i t i s h Medical Journal discussed t h e a p p a r e n t dangers involved in asbestos exposure.
Links between lung c a n c e r and asbestos have been suspected s i n c e t h e l a t e 1940s (Merewether 1949). Studies have shown t h a t a f t e r 20 y e a r s of exposure, asbestos workers mortality rates a r e double those of t h e g e n e r a l population.
Approximately 20 p e r c e n t of all asbestos workers die of lung c a n c e r (Selikoff e t al. 1964). However, non-smoking asbestos workers do not s u f f e r unusually high levels of lung c a n c e r . Selikoff's study concluded t h a t a n asbestos worker who smoked had 92 times t h e c h a n c e of dying of lung c a n c e r of non-smoking asbestos workers.
Not only do smoking asbestos workers have elevated lung c a n c e r rates, but also, quite significantly, s o do ex-smoking asbestos workers. While t h e o c c u r r e n c e of lung c a n c e r is lower among ex-smokers than smokers, i t is still considerably
higher t h a n among non-smokers (Selikoff and Hammon 1975). This would tend to un- dermine t h e p r e v a l e n t belief t h a t t h e ill e f f e c t s of smoking c a n , with time, b e com- pletely overcome, and instead s u p p o r t t h e heterogeneity-based idea t h a t t h e m o s t susceptible smokers tend to die within a t e n to twenty y e a r period a f t e r quitting t h e i r habit, and i t i s t h e surviving ex-smokers who n e v e r f a c e d p a r t i c u l a r l y g r e a t d a n g e r from t h e i r p a s t habit.
Asbestos e x p o s u r e also i n c r e a s e s a n individual's r i s k of obtaining mesothelio- ma, a r a r e tumor of t h e c h e s t or abdominal cavity. Most s u f f e r e r s of mesothelioma h a v e been exposed to asbestos. Mesothelioma i s not always occupation-related how- e v e r . High incidences h a v e been r e p o r t e d in r e s i d e n c e s n e a r industries where as- bestos were used, and t h e r e i s also a s t a t i s t i c a l e x c e s s of mesothelioma and o t h e r asbestos-related d i s e a s e s among household members of occupationally-exposed w o r k e r s (Stern 1977).
Alcohol is a n o t h e r major behavioral influence in heterogeneous susceptibility to environmental pollutants. Detoxification of alcohol places considerable s t r a i n on t h e human l i v e r and can, o v e r a period of y e a r s c a u s e permanent damage. A s t h e l i v e r i s also needed for t h e detoxification of a v a r i e t y of pollutants (insecticides,lead.etc.), t h e impairment of t h e l i v e r i n c r e a s e s t h e r i s k of t h e s e substances (Calabrese 1978).
Alcohol a b u s e i s also believed to b e a n influence on c a n c e r susceptibility. N o t only h a s alcohol been found to i n c r e a s e t h e probability of acquiring lung c a n c e r , b u t when accompanied by smoking, t h e r e is believed t o b e a synergistic, r a t h e r t h a n additive i n c r e a s e in c a n c e r r i s k s (Rothman 1975).
Finally, positive c o r r e l a t i o n s h a v e been found between u r b a n r e s i d e n c e and r e s p i r a t o r y illness. The T h r e e City Study found a p e r s i s t e n t e x c e s s in u r b a n dwellar's lead levels as compared to r u r a l populations. Lead i s believed t o c a u s e anemia and hyperactivity in children.
Acute a i r pollution episodes are a primarily u r b a n o c c u r r e n c e . In t h e s e in- cidents, e x t r a o r d i n a r y meterological conditions will lead to a n effective reduction in air volume, causing a r i s e in local pollution levels. Small water d r o p l e t s , often fog, have t h e n caused what i s essentially a r a i n of pollution. Acute a i r pollution in- cidents h a v e been associated with e x c e s s mortality and morbidity. During t h e p a s t 50 y e a r s , t h e r e have been a c u t e a i r pollution episodes in London, New York City, N e w Orleans, Minneapolis, a n d Tokyo t o name s e v e r a l ( S t e r n 1977).
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5. UNDERSTANDING POPULATION HETEROGENEITY IS IMPORTANT FOR THE REGULATION OF INDUSTRIAL AND ENYIRONMENTAL POLLUTION
Legislation t o r e g u l a t e industrial and environmental pollution h a s t r e a t e d heterogeneity in a v a r i e t y of ways. Some a c t s h a v e explicitly recognized h e t e r o - geneity, o t h e r s h a v e implicity recognized i t , while o t h e r s have ignored h e t e r o - geneity, concentrating instead on engineering-based solutions.
A major group of l a w s which explicitly recognize heterogeneous susceptibility are t h o s e with mandates t o p r o t e c t t h e most pollutant-sensitive g r o u p s within t h e population. F o r instance, infant susceptibility t o n i t r a t e and n i t r i t e toxicity played a key r o l e in t h e formulation of drinking water s t a n d a r d s (Calabrese 1978). Anoth- er example is t h e Clean Air A c t of 1969 which calls f o r t h e establishment of t h r e s - hold levels of pollution l o w enough to p r o t e c t "the m o s t sensitive group" against t h e "first a d v e r s e health effect" (Vaupel 1983). The U .S. Environmental P r o t e c t i o n Agency (EPA), in s e t t i n g a wide v a r i e t y of national ambient a i r quality s t a n d a r d s which are based on t h i s a c t h a s r e p e a t e d l y had to consider such threshold levels.
Other acts h a v e implicitly recognized heterogeneity, setting s t a n d a r d s t h a t r e q u i r e r e s e a r c h into v a r i e d susceptibility. For instance, t h e Occupational Health and S a f e t y A c t of 1970 simply o r d e r s t h a t n o worker develop exposure-related health impairments (Vaupel 1983). To e n f o r c e such a n a c t , i t i s n e c e s s a r y to d e t e r - mine t h e sensitivity of t h e most-sensitive worker.
In a d i f f e r e n t way, t h e "zero r i s k " approach-if something i s r i s k y , ban it-can also b e s e e n as a recognition of heterogeneity if t h e motivation for complete remo- val i s t h a t , f o r t h e most sensitive individuals, no s a f e level exists. In setting a z e r o s t a n d a r d for food additives t h a t might c a u s e c a n c e r , t h e Delaney clause of t h e F e d e r a l Food, Drug, and Cosmetic A c t a p p a r e n t l y taking into account t h a t no abso- lutely safe level e x i s t s f o r all individuals (Vaupel 1983) and t h u s i s indirectly influ- enced by heterogeneity considerations.
The Toxic Substances Control A c t of 1976 introduces a m o r e s u b t l e implemen- tation of heterogeneous consideration by calling f o r t h e inclusion of cost-benefit analysis in determining a c c e p t a b l e levels of new substances. R a t h e r t h a n automati- cally seeking a point which p r o t e c t s even t h e m o s t susceptible individual, t h i s act allows for t h e consideration of trade-offs between t h e increasingly g r e a t e r economic c o s t s involved in protecting more and more sensitive individuals.
Other environmental pollutant acts, however, have ignored t h e importance of heterogeneous susceptibility. The "natural levels of r i s k " a p p r o a c h s e e k s levels of pollution no g r e a t e r t h a n would exist in t h e environment without man's interven- tion. Vaupel (1983) points out t h a t such s t a n d a r d s have been proposed t o d e t e r - mine allowable levels of nuclear waste. Such limits d o not t a k e into account indivi- dual differences, assuming instead in t h i s c a s e t h a t as man as developed in t h e p r e s e n c e of radiation, low levels of radiation must p r e s e n t no g r e a t danger t o him.
S e v e r a l "engineering" pollution standards-that is, ones which s e e k s t o con- t r o l pollution not by examining i t s health implication, but instead by considering t h e mechanics of solving t h e problem-also overlook heterogeneity. For instance a number of pollutants have been limited t o lowest d e t e c t a b l e levels. Vinyl chloride, which is believed t o c a u s e l i v e r c a n c e r , has been r e s t r i c t e d by OSHA t o a n expo- s u r e level of 1 . 5 p a r t s p e r million. This i s a slight adaptation of t h e OSHA mandate which r e q u i r e s employees t o b e p r o t e c t e d t o "the e x t e n t feasible." This "feasibili- ty" level has a l s o been used in such areas as a i r pollution control which calls f o r t h e use of t h e "best p r a c t i c a b l e c o n t r o l technology" (Vaupel 1983).
6. CURRENT DEMOGRAPHICAL TRENDS CAN MASK THE PROGaESS AGAINST ENYTRON'MXNTAL POLLUTION
Having examined some of t h e heterogeneities most likely t o b e involved in varied susceptibility t o environment pollutants, i t would seem t h a t knowledge about r i s k variation could be applied t o major approaching demographic changes t o make some predictions about impending a l t e r a t i o n s in mortality statistics.
The aging of t h e population will probably r e s u l t in confusing signals about man's p r o g r e s s against environmental pollutants. The g r e a t e s t success against mortality in r e c e n t y e a r s h a s been achieved against h e a r t and c i r c u l a t o r y disease.
A s people have been living beyond what would, in p r i o r y e a r s , have been t h e i r h e a r t - r e l a t e d mortality, more are contracting c a n c e r , a disease in which most suc- cess against morbidity and mortality h a s o c c u r r e d at t h e younger ages. If t h e in- creasing number of elderly, with weakened enzyme and immune systems, s u f f e r , as would seem likely, h i g h e r and higher rates of pollutant-related c a n c e r mortality, i t will become important t o consider t h e p r i o r likelihood t h e elderly would have had of dying from c i r c u l a t o r y illness, s o as not t o i n t e r p r e t t h i s new demographic t r e n d in a purely negative light.
Increased urbanization may also affect pollutant mortality r a t e s , particularly in terms of r e s p i r a t o r y illness. Increased urbanization and t h e growing number of elderly persons may o f f e r a convincing argument f o r immediately increasing r e s e a r c h and o t h e r e f f o r t s against r e s p i r a t o r y disease.
The move towards g r e a t e r automation in t h e manufacturing s e c t o r and t h e growth of s e r v i c e jobs may help t o lower pollutant-related deaths as workers are removed from continuous, long-term exposure t o harmful pollutants and chemicals.
However, indoor pollution in hermetically-sealed office buildings has t h e potential t o become a major health concern, and i t should not b e presumed t h a t moving work- ers out of manufacturing will automatically move them towards g r e a t e r health.
7 . HETEROGENEXTY CAN BE RESPONSIBLlE FOE UNEXPECTED DEMOGRAPHIC
TRENDS
While major shifts in t h e population should have d i r e c t affect on t h e incidence of environmental pollutant-related illness, a variety of o t h e r possible changes may have strong indirect effects on mortality and morbidity rates (Vaupel and Yashin 1985a, b)
.
If, f o r instance, some pollutants r e a c t with acquired heterogeneities then tighter pollution controls will change heterogeneity distribution in t h e population.
If this o c c u r r e d one might observe changes in mortality patterns. The new mortali- ty will grow f a s t e r with a g e than before. One may even observe convergence o r even cross-over of t h e s e mortality curves.
If a pollutant is responsible f o r a particular cause of death, i t s elimination will not necessarily lead t o increases in life expectancy at every age. I t is quite possible t h a t some pollutants increase mortality almost exclusively among t h e most f r a i l individuals, thus promoting a n intensive selection process. Removing this pol- lutant would d e c r e a s e t h e mortality r a t e f o r some a g e groups, y e t at t h e same time mortality r a t e s might r i s e significantly within t h e next a g e interval, consequently leading t o a lowered life expectancy figure at t h a t age.
Some heterogeneity f a c t o r s such as smoking, alcohol consumption, and inade- quate nutrition can b e responsible f o r a multivariate impact on human organisms and produce different causes of death; t h e r e f o r e , medical p r o g r e s s against one particular cause of death in t h e presence of this contaminant can increase t h e ob- served mortality from a n o t h e r cause of death.
If t h e r e are s e v e r a l contaminants each responsible f o r s e v e r a l c a u s e s of death, then non-uniform p r o g r e s s against cause-specific mortality could a l s o pro- duce a decline in some mortality r a t e and growth in o t h e r s . Non-uniform p r o g r e s s toward lowering pollution levels c a n produce additional unexpected e f f e c t s on t h e population morbidity. For some diseases r a t e s will decline, f o r o t h e r s they will r i s e .
For instance, t i g h t e r pollution controls, if i t i s assumed such controls will have t h e i r g r e a t e s t e f f e c t on c a n c e r incidences, could eventually lead t o a n in- c r e a s e e i t h e r in c a r i o v a s c u l a r d e a t h s o r t o t h e r i s e of a major new group of mor- talities. Decreased smoking would also tend t o have t h e same r e s u l t .
An interesting point of speculation i s t h e indirect health e f f e c t s of mandatory r e t i r e m e n t ages. The removal of workers from hostile (heavily polluted) occupa- tion environments as t h e y r e a c h a g e s of progressively increasing susceptibility might be a n indirect health boon.
Extraordinarily impressive p r o g r e s s h a s been made against cardiovascular illness in r e c e n t y e a r s . The l a r g e s t remaining a r e a f o r a health breakthrough may well b e c a n c e r among h i g h e r a g e groups. If b r e a k t h r o u g h s comparable t o those in t r e a t i n g c i r c u l a t o r y disease o c c u r in t h i s field, t h e carcinogenic e f f e c t s of en- vironmental pollutants would became, de gacto, less significant. Assuming t h a t t h e susceptibility w a s d e c r e a s e d relatively equally throughout t h e population, pro- g r e s s against c a n c e r might well i n c r e a s e t h e importance of hypersusceptible c o h o r t s with o t h e r ailments: as they became increasingly t h e only people t o s u f f e r from environmental pollutant-related mortality, t h e i r problems would automatically draw g r e a t e r attention and assume higher p r i o r i t y in t h e policy field.
8. HOW TO MODEL HETEROGENEITY
Heterogeneity models use two s e t s of assumptions. One of them involves t h e functional form of t h e hazard function; t h e o t h e r i s concerned with t h e probabilis- t i c distribution of heterogeneity f a c t o r s .
If t h e variables t h a t influence hazard r a t e s can b e observed, one i s dealing with observed heterogeneity. T h e r e a r e s e v e r a l functional forms often used t o specify t h e hazard functions. Recently, one of t h e most widely used h a s been t h e proportional hazard model. In t h i s model, t h e hazard r a t e h ( t , z ) c a n b e described in terms of t h e p r o d u c t of t h e two function: p ( t ) , which depends only on time at a g e t , called t h e underlying hazard and g ( z ) , which depends only on t h e influential
variable:
In Cox (1972) model g ( z ) t a k e s t h e form:
where /3 i s a n unknown p a r a m e t e r which should b e estimated. The o b s e r v e d vari- a b l e z could specify, f o r instance, t h e level of t h e environmental pollution in some p a r t i c u l a r area.
Some of t h e h e t e r o g e n e i t y v a r i a b l e s are unobserved. The n a t u r a l question i s how c a n o n e develop t h e d a t a processing algorithms in t h e p r e s e n c e of t h e s e hid- den h e t e r o g e n e i t y f a c t o r s . The t r a d i t i o n a l way t o solve t h i s problem i s simply to i g n o r e t h i s kind of heterogeneity. However, some s t u d i e s show t h a t ignoring unob- s e r v e d influential f a c t o r s in mortality models may lead t o biases in p a r a m e t e r esti- mation ( E l b e r s and Ridder 1982; Gail, Wieand, and Piantadosi 1984; Vaupel and Yashin 1 9 8 5 ~ ) .
Thus in cases w h e r e estimation precision i s important, o n e should t a k e care t o c o n s i d e r unobserved heterogeneity. The manner of t r e a t m e n t depends on t h e ancil- l a r y information a b o u t unobserved variables.
9. MODELS OF UNOBSERVED BIOLOGICALLY STIPULATED HETEROGENEITY Vaupel, Manton and S t a l l a r d (1979) and Vaupel and Yashin (19B5a) focused on t h e analysis of hidden h e t e r o g e n e i t y in t h e model where h a z a r d functions c a n b e r e p r e s e n t e d in t h e form:
The i n h e r e n t factors t h a t influence mortality may b e modeled in t e r m s of h e t e r o - geneity v a r i a b l e s t h a t d o not change with age. This v a r i a b l e i s o f t e n called f r a i l t y in p r o p o r t i o n a l h a z a r d models. Calculations show t h a t f o r a r b i t r a r y distribution of z t h e c h a n g e s of a v e r a g e f r a i l t y in t h e population zt h a v e s o m e r e g u l a r i t y con- ditions.
More p r e c i s e l y a v e r a g e f r a i l t y in t h e c o h o r t d e c r e a s e s as t h e c o h o r t a g e s . Such changes of a v e r a g e f r a i l t y may p r o d u c e unexpected r e s u l t s in population dynamics. Among t h e f a c t s t h a t may b e r e g a r d e d as a r t i f a c t s of heterogeneity o n e c a n find t h a t individuals a g e f a s t e r t h a n o n e c a n o b s e r v e , t h e s u c c e s s of medical
programs may have negative consequences on mortality, and life expectancy, con- v e r g e n c e , and c r o s s o v e r s of t h e mortality c u r v e s f o r some g r o u p s of individuals in t h e population c a n b e a l s o t h e a r t i f a c t s of heterogeneity.
The widely used distribution of f r a i l t y i s Gamma distribution. I t t a k e s t h e fol- lowing density function:
The s t r a i g h t f o r w a r d calculation show t h a t f o r observed mortality p ( t ) in t h i s case t h e following expression is t r u e :
If
zo
is equal t o 1 then t h e formula f o r A t ) c a n b e simplified to:Combination of o b s e r v e d and unobserved heterogeneity in h a z a r d functions w a s analyzed in Heckman and S i n g e r (1982) f o r some econometric models. Vaupel and Yashin (1985b) analyzed some unexpected e f f e c t s of heterogeneity on popula- tion dynamics.
The influence of a wide v a r i e t y of p r o c e s s e s on human mortality leads to t h e models of changing o r a c q u i r e d heterogeneity. These models c a n b e analyzed through t h e framework of t h e following formal scheme.
10. MODELING OF ACQUIRED HETEROGENEITY
Let u s assume t h a t t h e duration of life f o r any individual in t h e c o h o r t depends on multidimensional p r o c e s s z t . The t r a j e c t o r i e s of t h e p r o c e s s e s d i f f e r from individual t o individual. The components may b e t h e concentration of pollu- t a n t s in t h e local environment, social and economic differences, behavioral fac- t o r s , etc.. The m o s t a p p r o p r i a t e way t o d e s c r i b e t h i s v a r i e t y i s to use a s t o c h a s t i c p r o c e s s model (Yashin, Manton, Vaupel 1985).
The dependence of t h e hazard r a t e on t h e values of t h e p r o c e s s zt may b e sim- plified in t e r m s of some p a r a m e t r i c function:
where a is t h e v e c t o r of unknown p a r a m e t e r s . The functional form of ( t , a , z t ) i s determined from special studies. T h e r e a r e r e s u l t s t h a t show t h a t f o r some p a r t i c - u l a r continuously distributed influential p r o c e s s t h i s function i s t h e q u a d r a t i c form of z t . For finite s t a t e continuous time stochastic p r o c e s s e s t h e dependence A t , z t ) on zt c a n be a n a r b i t r a r y function. The fundamental r e s u l t of t h e h e t e r o - geneity analysis i s t o establish t h e correspondence between observed mortality
@ ( t ) and mortality @(t ,z t ) conditional on p r o c e s s zt
.
This relationship is:where T i s t h e death time specified as a positive random variable.
Note t h a t t h e dependence @(t ,z t ) on unknown p a r a m e t e r s produces t h e depen- dence @(t ,a ) on t h e s e p a r a m e t e r s . If t h e available d a t a a r e a b o u t t h e death time of N individuals ( t l,t 2,
.. . .
. t N ) t h e n one can form t h e likelihood function:and use i t f o r p a r a m e t e r estimation.
If heterogeneous variation i s a p r o c e s s which changes in s t e p s o v e r time with a finite number of s t a t e s and a matrix of transition coefficients q i j ( t , a ) , t h e n t h e formula f o r Z ( t , a ) is as follows:
where q ( t ) are t h e solutions of t h e following o r d i n a r y nonlinear differential equations: '
where N is t h e number of states.
Very often d a t a about death times contains information about cause of death.
The influence of t h e p r o c e s s zt on t h e cause-specific mortalities f i ( t , z t ) c r e a t e s t h e situation where different causes of death become dependent. Traditional models of competing risk use t h e independence assumption which does not hold t r u e in models of heterogeneity with competing r i s k s .
I t t u r n s out t h a t even in t h i s c a s e one c a n develop a n a p p r o a c h which allows one t o organize data-processing algorithms using t h e maximum likelihood ap- proach. If hi (t , z t )
=
qpi ( t ,zt , a ) a r e t h e functional p a r a m e t r i c forms of t h e condi- tional cause-specific mortality then f o rxi
( t , a ) we c a n d e r i v e t h e formula:i i In t h e case when d a t a specifies t h e death times and causes of death ti ',t 2?,..
t h e likelihood function is:
when ik i s cause of d e a t h f o r k-th individual and m is t h e number of causes of death.
Yashin, Manton, and Vaupel (1985) considered s t o c h a s t i c p r o c e s s models of mortality and aging in t h e p r e s e n c e of heterogeneity t h a t c a n change o v e r time.
Continuous time and continuous state s t o c h a s t i c p r o c e s s e s were considered as a model f o r influential f a c t o r s . The finite s t a t e jumping p r o c e s s model w a s analyzed in Yashin (1984). Estimation p r o c e d u r e s and forecasting algorithms were a l s o analyzed in Y ashin, Manton, and S t a l l a r d (1985a,b).
11. CONCLUSION
In considering and implementing environmental pollution controls, a n under- standing and appreciation of t h e important r o l e played by human heterogeneity may b e one of t h e keys t o producing successful policy. Heterogeneity, both biolog- ical and acquired, c a n lead t o significant v a r i e t y in individual susceptibility. I t i s conceivable t h a t one individual might b e at no r i s k t o t h e harmful p r o p e r t i e s of a pollutant, while a n o t h e r individual might f a c e g r e a t l y increased levels of mortality from even low-level, infrequent exposure. Thus, while r e c e n t legislative attempts
t o limit environmental pollution have increasingly recognized t h e significance of heterogeneous r i s k c o h o r t s , much c a n still b e done t o t a k e differing r i s k s into ac- count.
Heterogeneity a l s o plays a n i n d i r e c t r o l e in man's study of environmental pol- lution. Competing r i s k s can confuse i n t e r p r e t a t i o n of s t a t i s t i c s r e l a t e d to man's p r o g r e s s against pollution, and t h e independent i n c r e a s e o r d e c r e a s e of d i f f e r e n t r i s k groups c a n c a u s e a corresponding d r o p or r i s e in morbidity and mortality. To help p r e d i c t t h e importance of such changes, heterogeneity can b e modelled in a v a r i e t y of ways t o give g r e a t e r insight into t h e e f f e c t of changes among d i f f e r e n t cohorts.
Methods developed f o r capturing unobserved heterogeneity show ways of in- c o r p o r a t i n g ancillary information into t h e models. Combining t h e s e models with measurement d a t a provides a n opportunity to develop numerical p r o c e d u r e s f o r p a r a m e t e r estimation as well as identification of t h e model.
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