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AMERICAN JOURNAL OF EPIDEMIOLOGY Copyright © 1976 by The Johns Hopkins University School of Hygiene and Public Health Vol. 104, Xo. 2 Printed in U.SA. THE CONTRIBUTION OF THE SOCIAL ENVIRONMENT TO HOST RESISTANCE 1 THE FOURTH WADE HAMPTON FROST LECTURE JOHN CASSEL 2 I count myself honored indeed to be included among those who have been chosen to present this, the Wade Hampton Frost Lecture. Unlike my predecessors in this series, I never had the privilege of knowing or meeting Dr. Frost, although of course I know many of his illustrious stu- dents. I do claim one unique experience, however; I read his collected papers when practicing in South Africa before I had ever heard of the word epidemiology, much less knew what it meant. In a real sense, then, those papers were my introduction to the whole field, and for this I must thank my very wise chief, Dr. Sidney L. Kark, who introduced me to the papers, particularly the section on tuberculosis. The thinking displayed in those articles opened my eyes to a new world and provided an opportu- nity to begin to understand what up until then had been to me a totally mysterious phenomenon, the explosive epidemic of tuberculosis I was witnessing in the African population for whom I was providing care. Perhaps, though, of all the words Frost wrote, the ones that have made the most impression on me have been his often quoted introduction to the reprinting of John Snow's papers (1) which starts, "Ep- idemiology at any given time is something more than the total of its established facts. It includes their orderly arrangement into chains of inference which extend beyond the bounds of direct observation." It is this "orderly arrangement into chains of infer- ence" which intrigues me and which I 'Presented at the 103rd Annual Meeting of the American Public Health Association in Chicago, IL, on November 18, 1975. 2 Department of Epidemiology, U. of North Caro- lina, Chapel Hill, NC 27514. think distinguishes creative epidemiologic studies from studies which may display considerable rigor in their methods but which are essentially pedestrian. The question then is, what guides us in developing these chains of inference? Unquestionably, in large part the answer is the model of disease causation which we (implicitly or explicitly) espouse. In Frost's day this model, stated in its most general form, was that disease occurred as a result of new exposure to a pathogenic agent. It was recognized, of course, that the conse- quences of such exposure would be deter- mined both by the pathogenicity of the agent and the degree of resistance or sus- ceptibility of the host. This relationship has now been extended and formalized into the well-known triad of host, agent and environment in epidemiologic thinking. Since Frost, the elucidation of host resist- ance factors has largely been the responsi- bility of the vastly expanded fields of biomedical research, such as genetics, mo- lecular biology, immunology, biochemistry and endocrinology; while epidemiology has continued to search for the effects of a vastly expanded array of pathogenic agents in the environment. The inferences drawn on the basis of such findings have been that, given a certain level of resistance (for whatever reasons), we should be able to explain the occurrence of disease as a result of exposure to these pathogenic agents. Rene Dubos (2) has recently pointed out, however, that this formulation, which may have provided a satisfactory basis for infer- ences in the 19th and early part of the 20th century when most diseases of interest (such as typhoid, cholera, smallpox or plague) were the result of agents of over- 107

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AMERICAN JOURNAL OF EPIDEMIOLOGYCopyright © 1976 by The Johns Hopkins University School of Hygiene and Public Health

Vol. 104, Xo. 2Printed in U.SA.

THE CONTRIBUTION OF THE SOCIAL ENVIRONMENT TO HOSTRESISTANCE1

THE FOURTH WADE HAMPTON FROST LECTURE

JOHN CASSEL2

I count myself honored indeed to beincluded among those who have beenchosen to present this, the Wade HamptonFrost Lecture. Unlike my predecessors inthis series, I never had the privilege ofknowing or meeting Dr. Frost, although ofcourse I know many of his illustrious stu-dents. I do claim one unique experience,however; I read his collected papers whenpracticing in South Africa before I had everheard of the word epidemiology, much lessknew what it meant. In a real sense, then,those papers were my introduction to thewhole field, and for this I must thank myvery wise chief, Dr. Sidney L. Kark, whointroduced me to the papers, particularlythe section on tuberculosis. The thinkingdisplayed in those articles opened my eyesto a new world and provided an opportu-nity to begin to understand what up untilthen had been to me a totally mysteriousphenomenon, the explosive epidemic oftuberculosis I was witnessing in the Africanpopulation for whom I was providing care.

Perhaps, though, of all the words Frostwrote, the ones that have made the mostimpression on me have been his oftenquoted introduction to the reprinting ofJohn Snow's papers (1) which starts, "Ep-idemiology at any given time is somethingmore than the total of its established facts.It includes their orderly arrangement intochains of inference which extend beyondthe bounds of direct observation." It is this"orderly arrangement into chains of infer-ence" which intrigues me and which I

'Presented at the 103rd Annual Meeting of theAmerican Public Health Association in Chicago, IL,on November 18, 1975.

2 Department of Epidemiology, U. of North Caro-lina, Chapel Hill, NC 27514.

think distinguishes creative epidemiologicstudies from studies which may displayconsiderable rigor in their methods butwhich are essentially pedestrian.

The question then is, what guides us indeveloping these chains of inference?Unquestionably, in large part the answer isthe model of disease causation which we(implicitly or explicitly) espouse. In Frost'sday this model, stated in its most generalform, was that disease occurred as a resultof new exposure to a pathogenic agent. Itwas recognized, of course, that the conse-quences of such exposure would be deter-mined both by the pathogenicity of theagent and the degree of resistance or sus-ceptibility of the host. This relationshiphas now been extended and formalized intothe well-known triad of host, agent andenvironment in epidemiologic thinking.Since Frost, the elucidation of host resist-ance factors has largely been the responsi-bility of the vastly expanded fields ofbiomedical research, such as genetics, mo-lecular biology, immunology, biochemistryand endocrinology; while epidemiology hascontinued to search for the effects of avastly expanded array of pathogenic agentsin the environment. The inferences drawnon the basis of such findings have beenthat, given a certain level of resistance (forwhatever reasons), we should be able toexplain the occurrence of disease as a resultof exposure to these pathogenic agents.

Rene Dubos (2) has recently pointed out,however, that this formulation, which mayhave provided a satisfactory basis for infer-ences in the 19th and early part of the 20thcentury when most diseases of interest(such as typhoid, cholera, smallpox orplague) were the result of agents of over-

107

108 JOHN CASSEL

whelming pathogenicity and virulence, isno longer of particular use in a technologi-cally developed society. In a modern soci-ety the majority of the citizens are pro-tected from these overwhelming agents andmost of the agents associated with currentdiseases are ubiquitous in our environ-ment. Dubos states it quite succinctly:"The sciences concerned with microbialdiseases have developed almost exclusivelyfrom the study of acute or semi-acuteinfections caused by virulent microorga-nisms acquired through exposure to anexogenous source of infection. In contrast,the microbial diseases most common in ourcommunities today arise from the activi-ties of microorganisms that are ubiquitousin the environment, persist in the bodywithout causing obvious harm under ordi-nary circumstances, and exert pathologicaleffects only when the infected person isunder conditions of physiological stress. Insuch a type of microbial disease, the eventof infection is of less importance than thehidden manifestations of the smolderinginfectious process and than the physiologi-cal disturbances that convert latent infec-tion into overt symptoms and pathol-ogy" (2).

Thus Dubos is stating that in societieswhere most disease agents are ubiquitousin the environment (and I believe hisstatement would cover most physiochemi-cal agents, not only microbiologic ones), afull understanding of the distribution anddeterminants of disease requires that weknow both the prevalence and toxicity ofthese agents and the determinants of thosefactors which change the relationship be-tween the host and these agents, thustransforming an innocuous, possibly sym-biotic, relationship to one in which clinicaldisease is the outcome.

The question facing epidemiologic in-quiry then is, are there categories or classesof environmental factors that are capableof changing human resistance in importantways and of making subsets of people moreor less susceptible to these ubiquitous

agents in our environment? When we havethought of these questions at all, we havebeen accustomed to think in rather generalterms of such things as nutritional status,fatigue, overwork or the like. I would sug-gest, however, that there is another cate-gory of environmental factors capable ofproducing profound effects on host suscep-tibility to environmental disease agents,and that is the presence of other membersof the same species, or more generally,certain aspects of the social environment.

The problem is that as soon as oneintroduces the concept of the potential roleof the social environment in disease etiol-ogy, the almost inevitable response is thatthis means stress and stress disease. I thinkthe simple-minded invocation of the wordstress in such thinking has done as much toretard research in this area as did theconcepts of the miasmas at the time of thediscovery of microorganisms. While therecan be no question regarding the use of theconcept of stress in the hands of the origi-nators of this term (as applied in a scien-tific sense to medicine), and that Selye andWolff (3), for instance, have made a signifi-cant contribution to our ideas about thenature of disease and its causes, the cur-rent uncritical subscription to what arethought to have been the ideas of theseinvestigators and the often erroneous inter-pretation of their theories by modern inves-tigators has frequently led to contradictoryfindings and inappropriate inferences.

First it is important to recognize thesemantic difficulties surrounding the use ofthe word "stress." By Selye and Wolffstress was envisaged as a bodily state, not acomponent of the environment. Thus Wolff(3) states, "I have used the word stress inbiology to indicate that state within aliving creature which results from the in-teraction of the organism with noxiousstimuli or circumstances, i.e., it is a dy-namic state within the organism; it is not astimulus assault, load symbol, burden, orany aspect of environment, internal, exter-nal, social or otherwise." While Wolff dem-

SOCIAL ENVIRONMENT AND HOST RESISTANCE 109

onstrated that this stress state (evidencedby neuroendocrinal changes) can be pro-duced by a variety of noxious stimuli,physical as well as psychologic, he did notattempt to define the characteristics or theproperties of these nonphysical (psycho-logic and/or social) noxious stimuli. De-spite such formulations, subsequent inves-tigators have tended to apply the term"stress" to these postulated noxious socialor psychologic stimuli, often quoting Wolfffor their justification. The use of the word"stressor" to indicate the environmentalnoxious stimulus and "stress state" ormore frequently "stress disease" to indi-cate the postulated consequences of suchexposure clarifies the semantic difficultybut highlights the more important concep-tual issue. Stated in its most general terms,the formulation subscribed to (often im-plicitly) by most epidemiologists and socialscientists working in this field is that therelationship between a stressor and diseaseoutcome will be similar to the relationshipbetween a microorganism and the diseaseoutcome. In other words, the psychosocialprocess under investigation is envisaged asa stressor capable of having a direct patho-genic effect analogous to that of a physico-chemical or microbiologic environmentaldisease agent. The corollaries of such aformulation are that there will be etiologicspecificity (each stressor leading to a spe-cific stress disease), and there will be adose-response relationship (the greater thestressor, the more likelihood of disease).There is serious doubt as to the utility orappropriateness of both of these notions.

Wolff himself stated quite explicitly thatthe action of physicochemical diseaseagents is different from psychosocial fac-tors in that the former have a directpathogenic effect by damaging and distort-ing structure and function, while the latteract indirectly (or, as he termed it, condi-tionally) by virtue of their capacity to actas signals or symbols (3). Thus, disease canoccur by virtue of a disturbance in thebalance between the organism and various

disease agents, as maintained by Dubos(2), and if this balance is mediated largelyby the neuroendocrine system, as has beenmaintained by Cannon (4) and Schoen-heimer (5) and widely accepted since, thenthe mechanism through which the signalsand symbols produced by the conditionalnoxious stimuli work presumably will be byaltering neuroendocrine secretions and lev-els in the body and thus changing thebalance. As will be referred to later, there isevidence from both animal and humanexperiments indicating that variations inthe social milieu are indeed associated withprofound endocrine changes in the exposedsubjects.

Viewed in this light, it is most unlikelythat any given psychosocial process orstressor will be etiologically specific for anygiven disease, at least as currently classi-fied. In other words, it no longer becomesuseful to consider a subset of existingclinical entities as "stress" diseases as alldiseases can in part be due to these proc-esses. Hinkle (6), arguing from the biologicevidence, supports this point strongly whenhe states: "At the present time the 'stress'explanation is no longer necessary. It isevident that any disease process, and infact any process within the living orga-nism, might be influenced by the reactionof the individual to his social environmentor to other people."

A more reasonable formulation wouldhold that psychosocial processes acting as"conditional" stressors will, by altering theendocrine balance in the body, increase thesusceptibility of the organism to directnoxious stimuli, i.e., disease agents. Thepsychosocial processes thus can be en-visaged as enhancing susceptibility to dis-ease. The clinical manifestations of thisenhanced susceptibility will not be a func-tion of the particular psychosocial stressor,but of the physicochemical or microbi-ologic disease agents harbored by the orga-nism or to which the organism is exposed.Presumably, the disease manifestationswill also be determined by constitutional

110 JOHN CASSEL

factors, which in turn are a function ofgenetic endowment and previous experi-ence.

Some reasonably convincing data existto support this point of view. For example,one of the striking features of animal stud-ies concerned with demonstrating thehealth consequences of a changed socialenvironment has been the wide range ofdiseases that have followed such changes.Alteration of the social environment byvarying the size of the group in whichanimals interact, while keeping all aspectsof the physical environment and diet con-stant, has been reported to lead to a rise inmaternal and infant mortality rates; anincrease in the incidence of arteriosclerosis;a marked reduction in the resistance to awide variety of direct noxious stimuli,including drugs, microorganisms and x-rays; an increased susceptibility to varioustypes of neoplasia; alloxan-produced dia-betes; and convulsions (7-15). Thus, inanimals at least, no specific type of "stressdisease" appears in response to changes inthe social milieu—changes which havebeen interpreted as "stressors." Rather,the animals appear to respond with avariety of diseases, the particular manifes-tation being determined by factors otherthan the disturbed social process. Theevidence from human studies is somewhatless direct but nevertheless still consistentwith this idea. A remarkably similar set ofsocial circumstances characterizes peoplewho develop tuberculosis (16) and schizo-phrenia (17, 18), become alcoholics (19),are victims of multiple accidents (20), orcommit suicide (21). Common to all thesepeople is a marginal status in society. Theyare individuals who for a variety of reasons(e.g., ethnic minorities rejected by thedominant majority in their neighborhood;high sustained rates of residential andoccupational mobility; broken homes orisolated living circumstances) have beendeprived of meaningful social contact. It isperhaps surprising that this wide variety ofdisease outcomes associated with similar

circumstances has generally escaped com-ment. To a large extent this has probablyresulted from each investigator usuallybeing concerned with only one clinicalentity so the features common to multipledisease manifestations have tended to beoverlooked.

One exception to this has been the studyby Christenson and Hinkle (22). In anindustrial study in the United States, theyhave shown that managers in a companywho, by virtue of their family backgroundand educational experience were least wellprepared for the demands and expectationsof industrial life, were at greater risk ofdisease than age-matched managers whowere better prepared. They found that thisincreased risk included all diseases, majoras well as minor, physical as well as men-tal, long-term as well as short-term. Afurther example illustrating this point isthe health consequences that follow thedisruption of important social relation-ships, particularly death of a spouse. It hasbeen shown that widowers have a deathrate three to five times higher than marriedmen of the same age for every cause ofdeath (23). It is difficult to conceive of aspecific etiologic process responsible for theincreased death rate from such diverseconditions as coronary heart disease, can-cer, infectious diseases and peptic ulcer,and it would appear more reasonable toconsider that the loss of the spouse in-creases the susceptibility of such men toother disease agents.

Of course this position that psychosocialfactors act as conditional or predisposingfactors rather than as direct pathogenicagents is no different from the positiontaken by the psychosomasists, who havemaintained quite specifically that psycho-logic factors should be regarded as predis-posing rather than direct etiologic agents indisease. Where it does differ is suggestingthat these order of factors will not beetiologically specific for any given disease(at least given the current clinical classifi-cation of diseases) and that research aimed

SOCIAL ENVIRONMENT AND HOST RESISTANCE 111

at searching for a specific subset of "stressdiseases" or attempting to link one type ofstressor to a single clinical manifestation islikely to be unproductive.

My position on this complete absence ofetiologic specificity (or putting it in an-other way, that the function of these psy-chosocial processes is to enhance suscepti-bility to all disease in general) may have tobe modified somewhat by relatively recentdevelopments. Henry (24) has shown that,in animal colonies, animals in the processof establishing their dominance show asympathetic adrenal medullary catechol-amine response and persistent elevatedblood pressures. The ones forced into sub-ordination, however, show more of thepituitary adrenal cortical response pattern,a pattern he feels is more consistent withdepression and all the disease manifesta-tions that have been associated withdepression and hopelessness. If this is trueit might be necessary to modify my stanceand admit there may be several clusters ofdiseases associated with different psy-chosocial situations.

Clarification of the outcomes to be ex-pected from exposure to these psychosocialprocesses is, however, only one of thedilemmas facing research in this area. Itprovides no guide as to what these proc-esses might be, much less how they are tobe measured.

One of the unfortunate controversiesthat has clouded research in this area hasbeen the one about whether such stressorsare invariant, affecting all people in asimilar manner, or whether they are idi-osyncratic, affecting each person differ-ently depending upon his personality, in-terpretation of the situation, and so forth.The position for the latter point of view(which might be summarized as "what isone man's meat is another's poison") hasrecently been stated quite succinctly byHinkle (6): "In view of the fact that peoplereact to their 'life situations' or socialconditions in terms of the meaning of thesesituations to them, it is difficult to acceptthe hypothesis that certain kinds of situa-

tions or relationships are inherently stress-ful and certain others are not." Others,including perhaps the majority of inves-tigators, have treated these factors not onlyas if they were invariant but as if they wereunidimensional, the presence of the factorbeing stressful, its absence beneficial.

Quite clearly, if the idiosyncratic pointof view is correct, much of the work toidentify universal or general stressors willbe futile and lead to contradictory andconfusing results. But equally clearly, thecontrary point of view ignores the proposi-tion that these processes do not have adirect pathogenic action but operate intheir capacity as signals or symbols trigger-ing off responses in terms of the informa-tion they are perceived to contain. And asthis perception will almost certainly be afunction of the differing personalities andthe salience of the experience to differentindividuals, it is hard to accept the notionthat certain social circumstances will al-ways, or even in the majority of cases, be"stressful." This dilemma can best beresolved, I believe, by two changes in ourthinking, changes which appear consistentwith most of the data and which conceiva-bly explain some of the existing contradic-tions. The first of these is that the extent towhich the postulated psychosocial proc-esses are generally noxious versus idiosyn-cratic in their action is largely a function ofour level of abstraction. If we can identifythe characteristics or properties of thosesignals or symbols which generally evokemajor neuroendocrinal changes in the re-cipients, we will have identified a generalclass of stressors even if the particularcircumstances or relationships creatingthose types of signals or symbols differ fordifferent people. Furthermore, if we canidentify the attributes of this class ofstressors, it may well be that the samerelationships or social circumstanceswithin a given culture (or, perhaps, subcul-ture) regularly produce such a class ofsignals. Secondly, the existing data haveled me to believe that we should no longertreat psychosocial processes as unidimen-

112 JOHN CASSEL

sional stressors or non-stressors, but ratheras two-dimensional, one category beingstressors, and another being protective orbeneficial.

The evidence supporting these points ofview comes from both animal and humanresearch. As has been indicated earlier,altering the social milieu of animals byincreasing the number housed togetherleads to marked changes in health status,even when all relevant aspects of the physi-cal environment and diet are kept con-stant. The biologic mechanisms throughwhich such changes are produced have alsobeen identified. Changes in group member-ship and the quality of group relationshipsin animals have been shown to be accom-panied by significant neuroendocrinalchanges affecting the pituitary, the adreno-cortical system, the thyroid and gonads(25, 26). These same endocrines are thoseresponsible in large part for maintainingwhat Schoenheimer (5) has termed "thedynamic steady state" of the organism, andthus, presumably, its ability to withstandchanges which would result from the actionof disease agents.

The questions of concern are, what arethe properties of the changes in this socialmilieu, and are there analogues in thehuman social system? The usual notionthat the crowding itself (that is, the physi-cal density of the population) is responsiblefor the deterioration in health status hasnot been sustained in human studies. De-spite the popularity of the belief thatcrowding is harmful to health, a review ofthe literature shows that for every studyindicating a relationship between crowdingand some manifestation of poor health,there is another equally good (or bad)investigation showing either no relation-ship or even an inverse one (27, 28). Fur-thermore, Hong Kong, one of the mostcrowded cities in the world, and Holland,one of the most crowded countries, enjoysome of the highest levels of both physicaland mental health in the world (29).

A careful review of the data reportedfrom these animal studies may hold a clueto these puzzles. In animals, an almostinevitable consequence of crowding is thedevelopment of a set of disordered relation-ships among the animals. These, whilemanifested by a wide variety of bizarre andunusual behaviors, often have in common afailure to elicit anticipated responses towhat were previously appropriate cues.Thus, habitual acts of aggression (includ-ing "ritualized aggression" in defendingthe nest), or evidence of acceptance ofsubordination on the part of one animal,fail to elicit appropriate reciprocal re-sponses on the part of another. In socialanimals under wild conditions, for exam-ple, the occupier of a nest will define a zonearound that nest as "home territory." Inva-sion of this territory by another animal ofthe same species will lead to a set of highlyritualized aggressive moves and counter-moves, rarely leading to bloodshed, butculminating in one or the other animal"signaling" capitulation. Under crowdedconditions the defending animal may initi-ate this ritual "dance," but the invadinganimal fails to respond in the anticipatedfashion. Instead he may lie down, go tosleep, attempt to copulate, walk away, ordo something which, for the situation, isequally bizarre.

This failure of various forms of behaviorto elicit predictable responses leads to oneof three types of responses on the part ofthe animals involved, the most common ofwhich is repetition of the behavioral acts.Such acts are always accompanied by pro-found neuroendocrinal changes, and pre-sumably their chronic repetition leadseventually to the permanent alterations inthe level of the hormones and to the degreeof autonomic nervous system arousal re-ported under conditions of animal crowd-ing. The fact that these behavioral acts arein a sense inappropriate, in that they donot modify the situation, can be expectedto enhance such hormonal changes. Under

SOCIAL ENVIRONMENT AND HOST RESISTANCE 113

these conditions it is not difficult to envis-age the reasons for the increased suscepti-bility to environmental insults displayedby such animals.

An alternative response on the part ofsome animals is to withdraw from the fieldand to remain motionless and isolated forlong hours on end. It is not uncommon toobserve some mice under crowded condi-tions crouched in most unusual places, ontop of the razor-thin edge of a partition orin the bright light in the center of theenclosure, completely immobile and notinteracting with any other animals. Suchanimals do not exhibit the increased pa-thology demonstrated by the interactingmembers (7).

The third alternative is for animals toform their own deviant groups that appar-ently ignore the mores and codes of behav-ior of the larger group. Thus, "gangs" ofyoung male rats have been observed invad-ing nests, attacking females (the equiva-lent of gang rapes has been reported), andindulging in homosexual activities. I amnot aware of any data on the health statusof these gang members, but according tothis hypothesis they also should not exhibitany increase in pathology.

These observations would suggest that atleast one of the properties of stressful socialsituations might be that the actor is notreceiving adequate evidence (feedback)that his actions are leading to anticipatedconsequences. While we do not as yet havethe appropriate instruments to measure inany direct fashion the extent to which sucha phenomenon is occurring in humans, it isnot unreasonable to infer that this phe-nomenon is highly likely to occur undercertain circumstances. First, it is probablethat when individuals are unfamiliar withthe cues and expectations of the society inwhich they live (as in the case of immi-grants to a new situation, or of individualsinvolved in a rapid change of social envi-ronment, such as the elderly in an ethnicenclave caught up in urban renewal), many

of their actions and the responses to theseactions would fall into this category andthus, if this suggestion is correct, theyshould be more susceptible to disease thanthose for whom the situation is familiar.Another circumstance in which this lack offeedback might occur would be under con-ditions of social disorganization. This,while still being far from a precise termwhich can be measured accurately, hasproved to be a useful concept in a numberof studies.

As indicated earlier, however, a fullerexplanation of the potential role of psy-chosocial factors in the genesis of diseaserequires the recognition of a second set ofprocesses. These might be envisioned asthe protective factors buffering or cushion-ing the individual from the physiologic orpsychologic consequences of exposure tothe stressor situation. It is suggested thatthe property common to these processes isthe strength of the social supports providedby the primary groups of most importanceto the individual. Again, both animal andhuman studies have provided evidencesupporting this point of view. Conger et al.(30), for example, have shown that theefficacy with which an unanticipated seriesof electric shocks (given to animals previ-ously conditioned to avoid them) can pro-duce peptic ulcers is determined to a largeextent by whether the animals are shockedin isolation (high ulcer rates) or in thepresence of litter mates (low ulcer rates).Henry (31) has been able to produce per-sistent hypertension in mice by placing theanimals in intercommunicating boxes alllinked to a common feeding place, thus de-veloping a state of territorial conflict. Hy-pertension only occurred, however, whenthe mice were "strangers." Populating thesystem with litter mates did not producethese effects. Liddell (32) found that ayoung goat isolated in an experimentalchamber and subjected to a monotonousconditioning stimulus will develop trau-matic signs of experimental neurosis while

114 JOHN CASSEL

its twin in an adjoining chamber and sub-jected to the same stimulus, but with themother present, will not.

The evidence from human epidemiologicstudies is somewhat more circumstantial,yet I believe not inconsistent with thesenotions, and it certainly suggests that it isworthwhile to pursue these areas of investi-gation.

I have selected a number of studieswhich illustrate the potential importanceof these twin themes, lack of appropriatefeedback to individuals and absence ofsocial supports. On some occasions thesehave been indexed by situations of rapidsocial change or social disorganization, onothers by attempts to measure the proc-esses more directly. I have deliberatelyselected examples which employ a varietyof research designs and which have exam-ined the phenomena in relation to a widevariety of health outcomes.

The first is an older study of our owndesigned to illustrate the potential impor-tance of rapid social change (33). It tookplace in the mountains of Appalachia,where the population had been isolatedfrom developing civilization for about 150years. In the early 1900's a factory locatedin one of these mountain coves, and overthe next 50-60 years, by deliberate com-pany policy, recruited its labor force fromthe surrounding mountain coves. By 1960the factory" was populated by about 3000workers living in the company town, eatingsimilar diets and doing the same work forthe same pay. They were composed of twogroups, however. First, there were thosewho were the first of their family to leavethe coves for this new and strange life(where relationships, rights and obligationswere no longer determined by kinship, andwhere personal identity and worth did notdepend on the family one came from) and,second, there were those whose fathers hadworked in the same factory before them.The company made no distinction betweenthese two groups in terms of work, pay or

promotion, and, in fact, the only way theycould be identified was by examining thecompany records to find out whether aparticular worker had had a relative of thesame name there before him. The hypothe-sis of the study was that the second group,by virtue of their previous experience,would be better prepared for the expecta-tions and demands of industrial living thanthe first group and should thus exhibitfewer signs of ill health. As indicated infigures 1 and 2, when health status wasmeasured by responses to the Cornell Med-ical Index and sick absenteeism, the pre-diction held true.

The second study, by Neser et al. (34), isan ecologic study in which the healthoutcome measured is no longer self-percep-tion of health or health behavior, but deathfrom stroke, and the index of the postu-lated psychosocial processes, social andfamily disorganization. For this purpose,all 100 counties of North Carolina were

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<-> 6

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I st Generation

2nd Generation

I st Generation

2nd Generation

Number oforgansystems

"Emotional"Componentsof CM.I.

21-30 31-40 41-50

AGEFIGURE 1. Health status measured by responses to

Cornell Medical Index (CMI), Appalachian study.Mean scores by age and generation status for thosepeople with 0 or 1 absence during 40 month period.(Figure reproduced by permission from Cassel andTyroler (33).)

SOCIAL ENVIRONMENT AND HOST RESISTANCE 115

o; 1200

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o

§ 900

g 600Ir-<ra.

300

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1st Generation

\ / 34 Years or under \

Z 5 10 15 20 25 30LENGTH OF SERVICE (YEARS)

FIGURE 2. Change in number of absences withlength of service, by generation status and age groups,Appalachian study, using least squares line of best fit.(Figure reproduced by permission from Cassel andTyroler (33).)

ranked on the basis of a social disorganiza-tion score which had been developed by Dr.Harvey Smith as part of an exercise for theplanning of mental health services. Thecomponents of the score are: family insta-bility (per cent of primary families withonly one parent present); per cent of illegit-imate births; rate of males sentenced toprison camps; per cent of population sepa-rated or divorced; and per cent of childrenunder 18 not living with both parents.

The ranked counties were then groupedby index severity of the score into five tiers,from the least to the most disorganized,and the stroke mortality rate for Black menfor the nine-year period 1956-1964 wascomputed, basing the population figure onthe 1960 census data (figure 3).

As can be seen, there is a marked gradi-ent in stroke mortality with increasingcounty index of social disorganization, thisbeing most evident in the younger agegroup. Other than social disorganization,there did not seem to be any particular

features that systematically differed be-tween these various tiers of counties. Notier clustered geographically (making itunlikely that some component of the wateror soil was responsible), nor were there anymajor differences in economic level or ac-cess to medical care. To test for the possi-bility of confounding by an economic fac-tor, however, a subsequent study of Jamesand Kleinbaum (35) expanded the originallist of indicators of social disorganizationand included a number of economic indica-tors as well. The resulting county scoreswere derived by factor analysis which pro-duced two factors, one labeled a socialinstability factor and the other socioeco-nomic. The death rates from stroke (lim-ited at this time to 45 to 54-year-oldnon-white males for 1960) is shown infigure 4.

The difference previously observed per-sists even when controlling for socioeco-nomic level, making it unlikely that thefindings can be explained on the basis ofpoverty.

No matter how carefully ecologic studiesare done, however, nor how unambiguoustheir results, the findings are always sus-

300

260

220

180

1i 140

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Index of Sociol DisorgonizaMon

Klow) — 5 (high)

35-44 45-54 55-64AGE

65-74

FIGURE 3. Stroke mortality for Black males inNorth Carolina by county index of social disorganiza-tion, 1956-1964. (Figure adapted by permission fromNeser et al. (34).)

116 JOHN CASSEL

8 0 r ^m H High SocialInstability Index

6 0 ' ^ M E H Low SocialInstability Index

40

20

Q HIGH LOWSOCIO-ECONOMIC STATUS

FIGURE 4. Hypertension-related deaths per 10,000by socioecologic stress levels in non-white males aged45-54 in North Carolina, 1960. (Figure adapted bypermission from James and Kleinbaum (35).)

pect due to the possibility of the ecologicfallacy. It is comforting then to find theseresults replicated by another study thatwas conducted in another locality by anindependent investigator. This study, con-ducted in Detroit by Harburg et al. (36),rank ordered all census tracts by variouscomponents of what they called stressscores which included residential and fam-ily instability, crime and density, andeconomic deprivation. The scores were alsosubjected to factor analysis, yielding thetwo factors of social instability and socio-economic status. Tracts having both theupper range for the instability score andlower range for the socioeconomic scorewere labeled high-stress tracts, and theconverse for the low-stress tracts. Withineach of these tracts a random sample offamilies was selected (with about an 89 percent acceptance rate). These family mem-bers were interviewed and had their bloodpressures measured under standard condi-tions by trained and standardized inter-viewers. Figure 5 shows that after control-ling for weight, blood pressure levels arehigher for Black males at all ages, butparticularly at young ages if they live in thehigh-stress areas.

It is interesting to note that in none ofthese three studies was the same relation-ship found for Whites. Two possible specu-lations can be advanced to explain thisapparent anomaly. The first of these re-

lates to the situation of Blacks. In animalexperiments, changes in the social milieuhave their most marked and dramaticeffects on the health and endocrine statusof subordinate animals, with dominantones showing the least effects (37). Perhapsthese findings reflect the subservient rolethat Blacks (until perhaps recently) havebeen forced to occupy in our society. Thesecond speculation is the possibility that inthe face of social disorganization Whiteshave more resources, including sources ofsocial support to help buffer their physio-logic processes from these effects.

The next study uses a further design,case control, and examines a phenomenonfirst described by a contemporary andcolleague of Frost, Jean Downes. In some ofher Eastern Health District studies,Downes reported that a small proportion ofschool children were responsible for a dis-proportionately large number of school ab-sences, that these tended to be the samechildren year after year, and that theycame from families in which other mem-bers had a disproportionately high rate ofchronic and emotional illness (38). Thisstudy also examined family cohesivenessand the supports available in such fami-lies.

Two pools of elementary school childrenwere identified in a sample of 18 Floridaschools in a study by Boardman (39). Fromthese pools, 100 families of children whohad consistently had the highest absenceexperience in two successive years wererandomly selected and matched by race,

fOhO

mo:

I

706050403020100

• • High Stress AreasI I Low Stress Areas

BELOW ABOVEMEDIAN MEDIAN

40-59RELATIVE WEIGHT (

AGE 25-39

FIGURE 5. Diastolic blood pressure levels by stressareas, age and weight in Black men in Detroit. (Figurereproduced by permission from Harburg et al. (36).)

SOCIAL ENVIRONMENT AND HOST RESISTANCE 117

sex, grade and school attended of the indexchild with 100 randomly selected familiesof low-absence children. An instrument tomeasure the concept of family competencewas developed by the investigator andapplied blind to each of the 200 families.The components of the family competencescore were: commitment of members tofamily group objectives; communication,or the ability of the group to arrive at aworking consensus on issues and problems;pride in family; self-confidence; judgment,or the ability to identify and weigh alterna-tives; creativity or resourcefulness; andparticipation, or the commitment of familymembers to a collective process in thecommunity, their contribution to a defini-tion of goals (39).

In addition, data on a number of possibleconfounding variables which might ac-count for the high absence rates were alsogathered from both groups of families.These variables were: number of familymembers with time-losing illnesses; pres-ence of father in the home; family size;number of preschool children; mother'sage; number of siblings younger than theindex child; grade, sex and school attendedof the index child; school absence record ofthe index child; number of chronically illfamily members; belief in education; socialposition; and race (39).

Figure 6 shows the mean competencescores of these two groups of families. Inthe scores, the non-matched confoundingvariables have been controlled by stratifi-cation in the case of social class and bystepwise partial correlation for the rest. Ascan be seen from the figure, families ofhigh-absence children consistently hadpoorer family competence scores (indicat-ing lower cohesiveness and support) thandid those of low-absence children. Thefamily members of the high-absence chil-dren were also found to have more illness ofall sorts than was true in the families of thelow-absence children. The study thus con-firmed Downes' original findings.

Perhaps one of the more dramatic find-

8

eroco +1.00

.80

.60

.40

.200

.20

.40

.60

.80-1.00

1.20

IaUJMa

&

I

II I Low Absence• I High Absence

DHIGH MEDIUM LOW

SOCIAL CLASSFIGURE 6. Family competence scores and school

absences in children by social class. (Figure repro-duced by permission from Boardman (39).)

ings is that of Michael Marmot (40), whowas impressed by the findings of the Japa-nese-Hawaiian-American heart studywhich showed that the incidence of coro-nary heart disease was higher in Japanesepeople living in Hawaii than in those livingin Japan and still higher for those living inCalifornia than in Hawaii. Furthermore,these differences could not be explained byvariations in any or all of the standard riskfactors. Marmot wondered what additionalfactors might explain the high rate ofcoronary heart disease among the Japaneseliving in California, and he speculated thatin the process of migration they may havelost important sources of social support inthe face of bewildering and rapid culturalchange.

He conducted a cross-sectional study ona sample of Japanese men living in Califor-nia and developed an instrument to mea-sure to what extent they had retained thevalues of traditional Japanese culture. Thecomponents of the instrument and theproportions of Japanese men giving "tradi-tional" answers to culture of upbringingquestions are shown in table 1. As a valida-tion of this instrument Marmot comparedscores obtained for these Californian Japa-

118 JOHN CASSEL

TABLE 1

Culture of upbringing: proportion of Japanese men living in California giving "traditional" answer on culture ofupbringing questions*

Question "Traditional" answer% Giving

"traditional"answer

Years in JapanAge left parents' homeEver lived on a farmSchool in JapanYears in Japanese language schoolReligion (growing up)Friends while growing upWife's place of birthWife schooled in JapanWife's school Japanese language

> 10 yearsOlder than 25YesYes> 5 yearsBuddhistMostly JapaneseJapanYesYes

30365836275560181949

* Table reproduced by permission from Marmot (40).

TABLE 2Distribution of scores on index, culture of upbringing,by generation, Issei (Japanese immigrants to US) and

Nisei (offspring of immigrants)*

A. Angina Pectoris

Index score Issei Nisei

Non-traditional

Traditional Japanese

Total

2.05.2

13.311.629.638.4

100

13.120.525.812.718.19.8

100

* Table reproduced by permission from Marmot(40).

nese born in Japan with those obtained forthose born in the US (table 2).

As can be seen from figures 7 and 8, theprevalence of coronary heart disease(whether measured as angina or as myo-cardial infarction by history or by electro-cardiogram criteria) was always higher inthose men who had retained less of theirtraditional cultural matrix.

To assure that these differences were notsimply a function of differences in diet ormajor risk factors in the two groups, Mar-mot then controlled for these by stratifica-tion, as shown in figures 9-12. In each case(except perhaps for nonsmokers) the samerelationship holds true.

One of the few cohort type studies in this

• I Traditionali i Non-traditional

INo. of men 504 906 716 808 494 293

UJ

B. Pain of Myocardial Infarction6r

• D loL

No. of menAge

I513 921

<45732 830

45-54505 299

>55FIGURE 7. Prevalence of coronary heart disease

(CHD): angina pectoris and myocardial infarction,measured by cardiovascular questionnaire, by cultureof upbringing in Japanese men living in California.(Figure reproduced by permission from Marmot (40).)

field (Nuckolls et al.) was concerned withcomplications of pregnancy as the outcome(41). Complete data were obtained from170 white married primiparae of similarage and social class, all delivered by thesame service. Social stresses were mea-sured by a cumulative life-change score, amethod developed by Holmes and Rahe

SOCIAL ENVIRONMENT AND HOST RESISTANCE 119

QXo

A. Age < 45

CL

^ B TraditionalI I Non-traditional

. I I0No. of men 510 920 729 827Age <45 45-54

FIGURE 8. Prevalence of coronary

503 298>55

heart disease(CHD): major electrocardiogram abnormalities (Min-nesota codes 1:1, 1:2, 7:1) by culture of upbringing inJapanese men living in California. (Figure reproducedby permission from Marmot (40).)

A. Age < 456 r

Q

5u. No. of menO

I^ H TraditionalI I Non-traditional

241 272 257 625

or

B. Age 45-54

6

I INo of men 304 217 406 577Dietary preference Japanese Western

FIGURE 9. Prevalence of definite coronary heartdisease (CHD) by culture of upbringing in Japanesemen living in California, controlling for dietary prefer-ence, Japanese or Western. (Figure reproduced bypermission from Marmot (40).)

(42) to assess the major life changes towhich an individual had had to adapt.Social supports, or as they were termed,psychosocial assets, were assessed by aninstrument developed by the investigatordesigned to measure the subject's feelingsor perceptions of herself (with particularreference to this pregnancy), her relation-ships with her husband, her extended fam-

Q

5 ou. No. of menO

^ H TraditionalI I Non-traditional

I266 437 129 228 68 166

oUl

ora.

B. Age 45-54 ,6 r

iD lNo.ofmen 310 310 202 239Blood Pressure Normal* Borderline*

160 215High*

FIGURE 10. Prevalence of definite coronary heartdisease (CHD) by culture of upbringing in Japanesemen living in California, controlling for blood pressurelevel. * WHO criteria. (Figure reproduced by permis-sion from Marmot (40).)

A. Age < 45

^ H Traditional. I I Non-traditional

Q

u. No. of menoD

294 483 144 308 49 98

B Age 45-548r

ora.

I INo. of men " 335 355 261 304 101 129Serum cholesterol (mg %) <22O 220 -25 9 >26O

FIGURE 11. Prevalence of definite coronary heartdisease (CHD) by culture of upbringing in Japanesemen living in California, controlling for serum choles-terol. (Figure reproduced by permission from Marmot(40).)

120 JOHN CASSEL

A. Age <45• TraditionalI I Non-traditional

Q

5 oNo of men 113 212 176 345 208 339

OUJ B Age 45-54

rra.

INo. of men

I I268 300 240 259

E X - CURRENTSMOKER SMOKER

191 212NEVERSMOKED

FIGURE 12. Prevalence of definite coronary heartdisease (CHD) by culture of upbringing in Japanesemen living in California, controlling for smokinghabits. (Figure reproduced by permission from Mar-mot (40).)

ily and her immediate community in termsof the support she was receiving or couldanticipate receiving. Both instrumentswere administered to the subjects beforethe 32nd week of pregnancy. After delivery,the records were reviewed blind for anyevidence of complications of pregnancy ordelivery. Among these patients, 47 per centhad one or more minor or major complica-tions, a rate comparable to the 50 per centfound in a national study using the samecriteria.

Figure 13 shows that in the presence ofhigh life changes both before and duringpregnancy, 90 per cent of women with lowassets had one or more complications ofpregnancy. With equally high life changescores but with a high support score, only33 per cent of women had such complica-tions. When life change scores were highprior to pregnancy but low during thepregnancy, the asset score was protective

but less so. Figure 14 shows that when thelife change scores prior to pregnancy werelow, the asset score was irrelevant.

In an intervention trial, Pless and Sat-terwhite (43) were concerned with the nu-merous psychologic handicaps faced bychronically ill children and their familymembers, handicaps that were seriouslyinterfering with function and appeared tobe immune to the interventions of twoeminent departments of the medical cen-ter, Pediatrics and Psychiatry. As an ex-periment, they recruited a number of laypersons to serve as sources of social sup-

100

5 80UJz zo ox j=60r- <5 —Zi40LU 55 Oi°20

8

^ •Soc ia l Supports HighI I Social Supports Low

IIHIGH LOW

LIFE CHANGE SCORE DURING PREGNANCYFIGURE 13. Complications of pregnancy by life

change score and level of social support: high lifechange score before pregnancy. Study of 170 whitemarried primaparae of similar age and social class, alldelivered by the same service. (Figure adapted bypermission from Nuckolls et al. (41).)

6 0

| O 20HO:zo II

I Social Supports HighI I Social Supports Low

u ^ ° HIGH LOWS o LIFE CHANGE SCORE DURING PREGNANCYa.

FIGURE 14. Complications of pregnancy by lifechange score and level of social support: low lifechange score before pregnancy. Study of 170 whitemarried primaparae of similar age and social class, alldelivered by the same service. (Figure adapted bypermission from Nuckolls et al. (41).)

SOCIAL ENVIRONMENT AND HOST RESISTANCE 121

port. These family counselors were givenlittle specific training but were carefullyscreened to insure they had the desirablequalities. Preference was given to a womanwho had coped with a chronically ill childof her own and each one was subjected to abattery of psychologic tests to measuresuch attributes as emotional stability, em-pathy, dedication, etc.

The families with chronically ill mem-bers were then randomized and each coun-selor was assigned six families in the treat-ment group, with the other group remain-ing as controls. Visits to the families weredetermined by the counselors' availabilityand the families' needs. The results at theend of one year, based upon a variety ofpsychologic scores, are shown in figure 15.

Taken alone, then, no one of these stud-ies is entirely convincing. Taken together,however, the results are more impressive.The study designs have varied to includeecologic, cross-sectional, case-control, co-hort and randomized controlled trial ap-proaches. The health outcomes havespanned a spectrum from self-reportedsymptoms and sickness behavior to levelsof blood pressure, complications of preg-nancy and death. The postulated psycho-logic stressors and social supports havebeen assessed by measures ranging fromindirect proxy indicators to more directand focused instruments. In each case apositive finding in the predicted direction

UJO

60

40

20

H StudyI I Control

IIMPROVED SAME WORSE

PSYCHOLOGIC STATUSFIGURE 15. Changes in psychologic status of chron-

ically ill children attending medical center pediatricand psychiatric departments after receiving counsel-ling from lay persons recruited to serve as sources ofsocial support. (Figure adapted by permission fromPless and Satterwhite (43).)

has been discovered. Clearly it would havebeen more desirable if these varied out-comes and/or approaches had been used onthe same populations or if different studydesigns had been used to study the sameoutcomes. The results, however, appearsufficiently encouraging to warrant furtherresearch and to add a further dimension toFrost's "orderly arrangement into chains ofinference."

If such research were to support theseideas, it would suggest the need for aradical change in the strategies used forpreventive action. Recognizing thatthroughout all history, disease, with rareexceptions, has not been prevented by find-ing and treating sick individuals, but bymodifying those environmental factors fa-cilitating its occurrence, this formulationwould suggest that we should focus effortsmore directly on attempts at further iden-tification and subsequent modification ofthese categories of psychosocial factorsrather than on screening and early detec-tion.

Of the two sets of factors, it would seemmore immediately feasible to attempt toimprove and strengthen the social supportsrather than reduce the exposure to thestressors. With advancing knowledge, it isperhaps not too far-reaching to imagine apreventive health service in which profes-sionals are involved largely in the diagnos-tic aspects—identifying families andgroups at high risk by virtue of their lack offit with their social milieu and determiningthe particular nature and form of the socialsupports that can and should be strength-ened if such people are to be protected fromdisease outcomes. The intervention actionsthen could well be undertaken by non-professionals, provided that adequateguidance and specific direction were given.Such an approach would not only be eco-nomically feasible, but if the notions ex-pressed in this paper are correct, would domore to prevent a wide variety of diseasesthan all the efforts currently being made

122 JOHN CASSEL

through multiphasic screening and multi-risk-factor cardiovascular intervention at-tempts.

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