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Hypersusceptibilicy to Occupational Hazards EULA BINGHAM A significant amount of time and effort is devoted to devising procedures, policies, and laws to protect workers from occupational hazards. The fact that workers vary greatly in their sensitivities to these hazards provides the rationale for discussing hypersusceptibility to occupational hazards and con- sidering it an important issue in the years to come. Examination of the topic of susceptible populations is likely to lead to the conclusion that this is a very emotional subject. This is because of the complexity of the issue and because hiring and placement practices have been based on questionable assumptions of hypersusceptibility. For exam- ple, women of childbearing age have often been excluded from certain jobs in order that, in the event of pregnancy, the fetus would be protected from possible birth defects resulting from exposure to teratogens in the work- place. The causal relationship between birth defects and specific occupa- tional exposures has not been demonstrated to any extent in human popula- tions (Wilson, 1977~. Unlike the case of thalidomide, where there is a clear association with birth defects, the data are lacking or not available to deter- mine whether comparable risks exist for women exposed in the workplace. Since risk assessment has become such an important element in our public posture on interventions regarding environmental exposures, one must ask certain questions; for example, why do we not demand the necessary data before assuming all women are a "susceptible population"? When an agent clearly has its toxic effect on germinal cells, why is only the female selected for protection? Another instance in which questionable hypersusceptibility results in dis 79

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80 EULER BINGHAM criminatory hiring practices is the sickle-cell trait, the incidence of which is between 7 percent and 13 percent among blacks but generally rare in the rest of the population (Gardner, 19721. Under normal conditions, blood from individuals with this trait functions as it should. However, people with the sickle-cell trait have been barred from certain occupations because of the possibility that they are at greater risk from hazards that compromise the oxygen-carrying capacity of blood. Before any individual is denied work because of belonging to a so-called high-risk group, sound scientific evi- dence should clearly demonstrate that that person is hypersusceptible to hazards in the workplace and that there is no reasonable way to protect that person from these hazards. Understanding hypersusceptibility requires careful analysis of complex scientific, medical, legal, ethical, and economic problems. To facilitate discussion, this paper will focus on examples of hypersusceptible groups, screening and monitoring procedures, and fairness in making decisions regarding special groups. HYPERSUSCEPTIBLE GROUPS A hypersusceptible group is defined by a characteristic or set of character- istics that increase the probability that members of the group are more susceptible than others to particular hazards. These characteristics, called risk factors, fall into two basic categories, genetic and life history. Genetic factors are inherited traits that determine the fundamental biochemical machinery with which an individual can deal with environmental insults. Genetic factors include sex, capacity for enzymatic detoxification and elimi- nation of harmful chemicals, and immunologic competence. In addition, certain developmental and metabolic abnormalities and predispositions to specific diseases can be inherited. Life-history factors are nongenetic forces that act through time to modify the body's ability to deal with environmental insults. These factors include age, illness, nutritional status, drug use, socio- economic status, behavioral traits, and occupational and ambient exposures to noxious agents. In-depth analyses of genetic and life-history risk factors have been presented elsewhere (Calabrese, 1978, 1985a, 1985b). The fol- lowing examples of some of the better-characterized genetic and life-history factors are presented to demonstrate determinants of hypersusceptibility. The most conspicuous genetic factor is sex. Despite considerable research, mostly in animals, there are few data that indicate significant sexual differences in susceptibility among humans (Calabrese, 1985a). In animal experiments, sexual differences in sensitivities to chemicals gener- ally range from negligible to tenfold, although for a few chemicals this difference may be as high as a hundred times. An extremely important point

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HYPIERSUSCEPTIBILI~ TO OCCUPATIONAL HAZARDS 81 to remember when trying to apply such data to humans is that the degree and direction of sexual difference in susceptibility depend on both the species of animal and the type of compound being tested. In addition, the data for all compounds indicate that neither sex has an overall advantage in susceptibil- ity. A more selective and sensitive indicator than sex for possible hypersus- ceptibility comes from direct analysis of metabolic abnormalities that may render certain individuals more sensitive to environmental insult Istanbul et al., 1972; Calabrese, 1978, 1985b). One such abnormality, glucose-6- phosphate dehydrogenase (G-6-P) deficiency, occurs in 11 percent of black American males but in other individuals and ethnic groups as well. The G-6- P enzyme plays a critical role in maintaining the structure of red blood cells. Therefore, persons deficient in the enzyme may be at greater risk from foreign agents such as carbon monoxide, lead, nitrate, nitrite, ozone, and radiation, which attack red blood cells. Another metabolic abnormality that increases the body's susceptibility to toxic chemicals is due to genetic variation in an enzyme called pseudocho- linesterase. This and a closely related enzyme, cholinesterase, are required for proper functioning of the nervous system. Anticholinesterase insecti- cides, which block these enzymes, have been developed because for a number of reasons humans are generally far less susceptible to their effects than insects. However, in humans there are numerous genetic variants of pseudocholinesterase, some of which are much more sensitive to anticholin- esterase agents. This results in significant individual differences in suscepti- bility to a class of compounds for which the potential for human exposure is very high. Individual differences can also occur in an important class of enzymes that detoxify and lead to the excretion of foreign compounds (Calabrese, 1978, 1985b). An example is catalase, which detoxifies highly reactive forms of oxygen that are produced in the body by exposures to ozone or radiation. An estimated 5 million Americans are deficient in catalase and therefore may be at greater risk to ozone and radiation toxicity. Differences in another detoxi- fying enzyme, glucuronyl transferase, leads to Gilbert's syndrome in about 6 percent of the normal adult population. In addition to a decreased ability to excrete normal metabolic wastes, people with Gilbert's syndrome are less able to clear foreign substances such as polychlorinated biphenyls (PCBs) from their bodies and are therefore more susceptible to the adverse effects of exposure to these chemicals. In contrast to deficiencies in detoxifying enzymes, there are examples of elevated levels of enzymes that increase the toxicity of foreign agents (Cala- brese, 1978, 1985b). Approximately 45 percent of the American population may be at greater risk to the carcinogenic effects of polycyclic aromatic

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82 EUI~ BINGlI~M hydrocarbons (PAHs), a common class of pollutants found in combustion products and cigarette smoke, because their bodies produce larger quantifies of an enzyme called aryl hydrocarbon hydroxylase (AHH). As one of a group of enzymes known as mixed-function oxidases, AHH metabolizes PAHs to highly reactive compounds that combine with, and thus alter the functions of, normal cellular constituents such as DNA. A large body of evidence suggests that these reactions initiate processes that eventually lead to cancer; therefore, persons with elevated levels of AHH are at greater risk from cancer caused by PAHs. Abnormalities in metabolic processes, other than those that deal directly with toxins, can also lead to hypersusceptibility (Stanbury et al., 1972; Calabrese, 1978~. Cystinosis, cystinuria, and tyrosinemia are genetic disor- ders that affect kidney function. These disorders may act in concert with, and thus render the kidney hypersusceptible to, compounds such as heavy metals, which damage the kidney. Hypersusceptibility may result from interactions of compounds with other abnormal biological systems (Calabrese, 1978, 1985a, 1985b). Low levels of serum alpha antit~ypsin (SAT), a blood component that regulates repair processes in the lung, render the lung more susceptible to respiratory irri- tants. SAT deficiencies occur in 4 percent to 9 percent of individuals of northern European descent. Defects in the immunologic system may also lead to hypersusceptibility. For example, decreased immunoglobulin A makes the lung more sensitive to respiratory irritants. More commonly, the immunologic system overreacts to foreign agents. An estimated 2 percent of the work force will develop a hypersensitive reaction when exposed to isocyanates. When one examines these genetic differences that may have the potential for causing varying toxic responses to chemicals, it is clear that many of these traits can be easily and accurately tested for. However, the relation- ships between these traits and the risk of occupational disease are far from clear. At present, it is not possible to determine specifically which, if any, individuals are at increased risk due to genetic differences. Attempts to "select out" susceptible individuals are very uncertain and have unknown effects on reducing occupational disease. Immunologic, metabolic, and other genetic factors that govern hypersus- ceptibility are not static but are modified throughout a person's life. The most inescapable life-history factor is age (Calabrese, 1978~. From concep- tion to birth, the developing fetus relies on the mother's detoxification sys- tem for protection from foreign agents. A few months after birth, an infant's metabolic detoxification system is fully developed, but the immunological system will continue to mature for 10 to 12 years and then begin a slow decline in function. Diminished immunologic competence in the very young

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lIYP~SUSCEPTIBILI~ TO OCCUP'ION~L HAZARDS 83 and the very old makes these populations more susceptible to infectious disease, respiratory irritants, and carcinogens. These two populations may also be at greater risk from some ingested pollutants. For instance, the higher rates of intestinal absorption of metals such as lead among the young and the slower excretion rates for flouride among the old may increase the respective dangers of these agents for these two age groups. In the working population, long-term processes of aging may not affect susceptibility as much as daily and seasonal variations in biological pro- cesses (Calabrese, 19781. Although not well studied in man, these cycles have been shown to play important roles in the sensitivities of experimental animals to hazardous agents. An example of a relatively long-term cycle is pregnancy, which, because of its dramatic physiological effects on women, may be overly stressed as a risk factor. An objective view of the topic reveals much speculation but little evidence that pregnancy in normal, healthy women leads to increased sensitivity to occupational hazards (Wilson, 1977; Calabrese, 1985a). Many illnesses increase sensitivity to occupational hazards. In addition to the genetic disorders that have been mentioned, numerous infectious and noninfectious diseases damage organs and reduce their tolerance to foreign agents (Calabrese, 1978~. For example, diseases can reduce the tolerance of the kidney to heavy metals and flouride, the liver to chlorinated hydrocar- bons, the lung to respiratory irritants, and the heart to numerous chemicals. In developed countries, infectious disease is probably superseded by behavioral traits as a cause of hypersusceptibility to occupational hazards (Calabrese, 19781. The most widespread deleterious behavioral trait is tobacco smoking. This habit increases the body's susceptibility to legions of agents such as infectious pathogens, heavy metals, hydrocarbons, carcino- gens, and respiratory irritants. The habitual use of alcohol and other drugs also lowers the body's tolerance to many compounds, including lead, pesti- cides, and PCBs. In underdeveloped nations, one would expect suboptimal nutrition to be a key determinant of hypersusceptibility. Unfortunately, this may also be true of sizable populations in developed countries, including the United States, where dietary deficiencies are found in children of the poor. However, insufficient intake of key nutrients such as vitamins C and E, magnesium, riboflavin, and protein is widespread in the working population. These forms of malnutrition may cause significant increases in susceptibility to a large number of industrial hazards (Calabrese, 1978~. A final factor to consider when discussing hypersusceptibility to a particu- lar agent is previous and ongoing exposures to other agents, both in the workplace and in the ambient environment. For cumulative toxins like lead, it may be safe to say that, regardless of the source of exposure, the degree of

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84 EUI~ BINGH~M toxicity and risk from future exposures is more or less related to body burden ofthe toxin. If a system exists for monitoring the amount oftoxin in the body, as is the case for lead, then it is relatively easy to prevent the effects of excessive exposure. For exposure to multiple agents, particularly those that are difficult to analyze in the body, the risk from future exposures will be difficult to predict. This will be especially true where large differences occur in the structures and modes of action of the confounding agents. Another complicating aspect of multiple exposure is the control of exposures outside the workplace. The technical, ethical, and legal obstacles to reducing ambi- ent exposures of workers may force companies to relocate in areas where either there are lower numbers of hypersusceptible workers or outside expo- sures are lower or both. Complex and often synergistic interactions of genetic and life-history factors determine the overall health of a worker and his susceptibility to occupational hazards. Hypersusceptibility may result from one major risk factor or the coexistence of numerous minor risk factors. Overall good health and compensatory mechanisms may overcome the effects of a major risk factor for hypersusceptibility. Conversely, the summation of minor risk factors or the presence of an undetected major risk factor may render an apparently normal individual hypersusceptible to an occupational hazard. Although much has been learned about risk factors, it is difficult to deter- mine precisely which workers will exhibit hypersusceptibility. Caution must therefore be exercised when advising workers as to who is and who is not safe from occupational exposures. SCREENING AND MONITORING Given the underlying complexities, identification of hypersusceptible workers poses an important challenge to occupational health professionals. The traditional activities of occupational health are identifying and measur- ing exposures to occupational hazards, determining adverse health effects of these exposures, and devising means for controlling hazards and preventing adverse health effects. To cope with hypersusceptibility, these activities must be expanded to include identifying factors that predispose workers to increased risk, identifying populations of hypersusceptible workers, devel- oping procedures for screening and monitoring for hypersusceptibility, and designing measures to protect hypersusceptible workers. In many cases, occupational hazards are identified by observations of increased morbidity or mortality among specific populations of workers. This often requires the careful and painstaking efforts of epidemiologists. Laboratory experiments are conducted to gain further understanding of the relationships between known hazards and occupational disease and to pre

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HYPERSUSCEPTIBILI7~Y TO OCCUP~TIOI!IAlL GIZZARDS 85 diet problems before they are detected in the workplace. It is often difficult to relate results from laboratory experiments to humans because the experi- ments use specific species, strains, and sexes of inbred animals that have been raised under carefully controlled conditions. This is done to reduce biological variability that might obscure relationships between disease and exposure to agents. However, biological variability,is the basis of hypersus- ceptibility. Other experiments are therefore conducted to compare differ- ences in sex, strain, and species, and "normal" versus "abnormal" animals. Although often difficult to extrapolate to humans, data from this type of research provide scientists with valuable clues of what to look for when - identifying hypersusceptibility in workers. This research is having a great impact on medical screening, monitoring, and early identification of adverse health effects. Medical screening Is a procedure that usually takes place prior to employ- ment (Levy and Wegman, 19831. One of the purposes of medical screening is to determine whether an individual is at increased risk of developing disease in the work environment. Thus, a medical screen should include determination of genetic and life-history factors relevant to hazards encoun- tered in the workplace. Screens for genetic risk factors often use laboratory tests whose validity depends on three requirements: (1) the tests must be sensitive and specific for the traits being tested; (2) there must be a clear relationship between these traits and disease resulting from exposures to hazards encountered in the workplace; and (3) it should be economically feasible to apply the test to populations of workers exposed to a particular hazard. To date, a few tests for genetic risk factors meet these requirements only partially (Calabrese, 1978; Lappe, 19834. Forinstance, there are tests for low levels of serum antit~ypsin activity, which predict chronic obstruc- tive lung disease in coal miners; for glucose-6-phosphate dehydrogenase deficiency, which indicates susceptibility to red blood cell destruction caused by exposure to ozone or hemolytic chemicals; for sickle-cell anemia and sickle-cell trait, both of which decrease one's tolerance to oxygen depri- vation; and for allergic reactions to organic chemicals such as isocyanates. Future advances in biomedical research will undoubtedly produce addi- tional useful screening tests for genetic risk factors. Initial screening for life-history factors does not normally require exten- sive laboratory tests. Most of the needed information can be gathered by questionnaire and physical examination (Levy and Wegman, 19831. How- ever, initial findings or the presence of particular hazards in the prospective employee's workplace may require further laboratory evaluation. For exam- ple, persons previously employed as lead workers should have their blood lead levels checked. At present, when conducting screens for hypersuscepti- bility, the high degree of relevance of life-history information and the ease

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86 EULA BINGE with which it can be gathered make life-history factors more important than genetic factors. In addition to preliminary screening for hypersusceptibility, ongoing monitoring of workers and the workplace is often carried out. This is done to identify hazards, determine workers' exposure to hazards, and detect ill- ness. Traditional monitoring for hazardous agents uses instruments placed in the workplace or worn by workers. Sampling and analysis of data collected by these instruments are used to determine workers' probable exposure to hazardous agents and allow companies to comply with laws regulating expo- sure levels. A newer approach to monitoring relies on analysis of biological samples, usually blood or urine (Baselt, 1980; Levy and Wegman, 1983; Alessio et al., 1984~. Biological monitoring is used to measure the levels of toxins in the body and biological responses to these toxins. In many cases, biological monitoring may be more appropriate than traditional means of monitoring because it can more accurately determine the level of a toxin in the body. It allows not only for idiosyncrasies of exposure in the workplace but also for biological variability among workers. Biological monitoring relates to the problem of hypersusceptibility in three ways: (1) it makes it possible to identify workers who are at increased risk due to abnormally high body burdens or who display greater biological responses to toxins; (2) exposures can be more carefully monitored for workers at greater risk because of accompanying genetic or life-history factors; and (3) measure- ments of preclinical biological responses to toxins may be the best means for predicting and avoiding frank illness. One form of biological surveillance that holds great promise is genetic monitoring. Unlike genetic screening, which looks for inherited familial traits that might contribute to hypersusceptibility, genetic monitoring uses cytogenetic techniques to examine chromosomes directly for damage result- ing from environmental insults (Baselt, 1980; Levy and Wegman, 19831. Genetic damage can also be detected indirectly by looking for abnormal degradation products of chromosomal DNA in urine (Weinstein, 1983~. Chemicals that cause cancer and birth defects often exert their effects by reacting with chromosomal DNA. This damaged DNA is removed by cellu- lar repair processes and excreted in urine. Analysis of these excretion prod- ucts yields valuable insight into types and levels of exposure and the degree of hypersusceptibility to agents that damage chromosomes. It is always with caution that comments regarding biological monitoring are presented because, by its very nature, certain types of biological moni- toring are reflective of a "public health failure"; that is, the failure becomes apparent after exposure and perhaps after sentinels of injury are produced. The first line of defense remains environmental monitoring. Biological monitoring, however, can provide important and essential information in

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HYPERSUSCEPTIBILI7~Y TO OCCUP~IONAlL H~Z,JRDS 87 certain situations, for example, monitoring the urine of hospital workers who have the potential for exposure to antineoplastic drugs. FAIRNESS At various times during life, everyone exhibits one or more forms of hypersusceptibility. In addition to these common forms of hypersusceptibil- ity experienced by all, each person is likely to belong to smaller subpopula- tions with unique hypersusceptibilities. Society has long recognized and made special provisions for protecting hypersusceptible groups such as the young, the aged, and the sick. Advances in science and medicine are increasing man's ability to detect and remedy more forms of hypersuscepti- bility. Decisions based on these findings are raising issues of ethics, law, and the distribution of costs end benefits (Lappe, 1983~. Central to these issues is a basic premise of public health that states that society has an obligation to provide all persons equal protection against avoidable health hazards. Ide- ally, this means establishing legally permissible exposure levels that protect even the most sensitive individuals. However, questions of feasibility may necessitate special measures for hypersusceptible groups. There are three requirements for fair application of these special measures: (1) the need for special protective measures must be clearly established; (2) intervention measures must be adopted to deal with actual risks; and (3) these measures must provide the greatest degree of protection consistent with the individual freedom. Where the scientific evidence of risk is uncertain, one must weigh the gravity of the potential adverse effect before implementing protective measures. If the adverse effect is severe and irreversible (cancer, for exam- ple), then a strict protective approach must prevail. If the adverse outcome is relatively benign and reversible (such as mild dermatitis), then a watchful, waiting, de minimis approach could be taken that would lead to implementa- tion of protective measures when symptoms began to appear. The most difficult task in providing special consideration for hypersus- ceptible workers may be balancing the right of protection from hazards with the right of access to jobs. Clearly, hypersusceptible workers whose condi- tions can be easily accommodated without interfering with job performance should not be subject to job discrimination. On the other hand, there may be no alternative but to exclude certain workers from jobs that pose hazards for which no effective protective measures can be taken or when a worker's condition significantly interferes with his work performance or endangers others. Unfortunately, there are large gray areas in which judgments will be more difficult. The true nature of hypersusceptibility is just emerging from the shadows of speculation and myth. It is hoped that research in this vital area will

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88 EU~ BINGH~M flourish and produce information needed to make decisions on complex issues that affect all of us. It is further hoped that information gained from this research will be clearly and freely communicated in such a way as to ensure the greatest possible joint participation of labor, management, and government in decision making. REFERENCES Alessio, L., A. Berlin, and R. R. Boni. 1984. Biological Indicators for the Assessment of Human Exposure to Industrial Chemicals. Luxembourg: Commission of the European Communities. Baselt, R. C. 1980. Biologic Monitoring Methods for Industrial Chemicals. Davis, Calif.: Biomedical Publishers. Calabrese, E. J. 1978. Pollutants and High-Risk Groups: The Biological Basis of Increased Susceptibility to Environmental and Occupational Pollutants. New York: John Wiley & Sons. Calabrese, E. J. 1985a. Toxic Susceptibility: Male/Female Differences. New York: John Wiley & Sons. Calabrese, E. J. 1985b. Uncertainty factors and interindividual variation. Regulator Toxicol- ogy and Pharmacology 5: 190- 196. Gardner, E. J. 1972. Principles of Genetics. New York: John Wiley & Sons. Lappe, M. 1983. Ethical issues in testing for differential sensitivity to occupational hazards. Journal of Occupational Medicine 25:797-808. Levy, B. S., and D. H. Wegman. 1983. Occupational Health: Recognizing and Preventing Work-Related Disease. Boston: Little, Brown. Stanbury, J. B., J. B. Wyngaarden, and D. S. Fredrickson. 1972. The Metabolic Basis of Inherited Disease, 3rd ed. New York: McGraw-Hill. Weinstein, I. B. 1983. Monitoring for DNA adducts as an approach to carcinogen infection. Annual Review of Public Health 4 :409-413. Wilson, J. G. 1977. Teratological effects of environmental chemicals. Federation Proceed- ings 236: 1698.