BIOLOGIC MARKETS OF SUSCEPTIBILITY AND EXPOSURE

Biologic markers of susceptibility and exposure are intimately related in the evaluation of populations at risk for effects of xenobiotics. Although objective indicators of exposure, such as excreted metabolites or DNA adducts, are often convenient to identify a population at risk, the problem might be much more complex. For example, members of a population can vary widely in their susceptibility; a population defined as being at risk in the absence of knowledge of susceptibility might consist mostly of people who are not susceptible and therefore are not at risk or are susceptible to various degrees. This complication is particularly pertinent for diseases like cancer which have a long latency period and can involve a sequence of biologic changes. The situation can be less complex in the case of toxic responses that are related directly to a toxicant or its metabolites. Because of those fundamental principles, linking exposure to disease is difficult when large fractions of the population are not susceptible. For example, the tobacco industry maintains that smoking does not cause cancer, on the grounds that 95% of smokers never develop cancer. The power of biologic markers of exposure can be increased if they are linked to biologic markers of susceptibility and effect. Making that linkage provides a means to identify a real high-risk group among those exposed and can also provide an understanding of the mechanisms of disease.

POPULATIONS AT RISK

A major thrust of environmental-health research has been in the definition of acceptable magnitudes of exposure in the workplace and environment—usually without adequate data on effects on individuals or populations. Definition of risk with biologic markers can provide objective information concerning the effects of exposure on individuals and populations. This information can, in turn, be used to design cost-effective strategies of mitigation and is related directly to the ethical and practical issues discussed in Chapter 1.

About this PDF file: This new digital representation of the original work has been recomposed from XML files created from the original paper book, not from the original typesetting files. Page breaks ar to the original; line lengths, word breaks, heading styles, and other typesetting-specific formatting, however, cannot be retained, and some typographic errors may have been accidentally inserted. P use the print version of this publication as the authoritative version for attribution.

The section following immediately discusses nephrotoxicity. Discussions of genitourinary cancer follow later in the chapter.

Hereditary Susceptibility to Nephrotoxicity

Hereditary renal conditions are a documented but infrequent cause of end-stage renal disease (ESRD). The most prevalent hereditary renal disease is cystic kidney disease, which accounts for 3.4% of the cases of ESRD.

Other hereditary or congenital renal disease accounts for 0.9% of the cases of ESRD (NIH, 1993). An intriguing observation regarding the relationship between hereditary factors and ESRD comes from a case-control study of 325 men in which occupational exposure was sought as an etiologic explanation of their ESRD. Only patients whose diagnoses were compatible with toxicant-induced renal injury were included in the analysis; patients with other known causes of renal failure were excluded. That ESRD was most strongly associated with a family history of renal disease (odds ratio, 9.30:1) (Steenland et al., 1990), not with occupational exposure, suggested the presence of hereditary susceptibility.

Substantial evidence supports a sex-related predilection for susceptibility to various nephrotoxicants. For example, male rats are more sensitive than female rats to the nephrotoxic effects of carbon tetrachloride and aminoglycoside antibiotics (Bennett et al., 1991). In contrast, Moore et al. (1984) demonstrated a higher susceptibility of women than of men to the nephrotoxic effects of aminoglycoside antibiotics. In any case, there seems to be a sex-related effect in both rats and humans; whether these differences are genetic in origin remains to be determined.

Direct evidence of race as a risk factor in toxicant-induced renal injury is lacking, but blacks and some other minority groups are highly susceptible to other forms of renal disease, such as has been demonstrated for the renal disease due to hypertension and diabetes mellitus (see Chapter 2) (NIH, 1992).

Inherited renal disorders might influence susceptibility to toxic injury. The potential impact of genetic factors on the renal response to environmental agents has not been widely appreciated or reviewed. One important and complicating aspect is the highly variable penetrance or expression of most of the genetic abnormalities that involve the kidney. Many people who carry genes for renal abnormalities might be only mildly affected or remain completely asymptomatic for many decades. Although it might be relatively easy to identify the first person in a genetic line with overt clinical manifestations of genetic kidney disease, a much larger pool of asymptomatic people might also be at higher risk than normal for damage from exposure to biohazards.

A number of inherited disorders affect renal development or structure; these disorders have been extensively documented, and their clinical features

his new digital representation of the original work has been recomposed from XML files created from the original paper book, not from the original typesetting files. Page breaks ar hs, word breaks, heading styles, and other typesetting-specific formatting, however, cannot be retained, and some typographic errors may have been accidentally inserted. P this publication as the authoritative version for attribution.

are well described, as are the various modes of inheritance (Brenner and Rector, 1986; Fisher and Brenner, 1989). The best-studied among those diseases are autosomal dominant (adult) polycystic kidney disease, autosomal recessive (infantile) polycystic kidney disease, hereditary nephritis (Alport's syndrome), and hereditary osteoonychodysplasia (nail-patella syndrome).

Many inborn errors of metabolism can also have a major, if not primary, impact on the kidney. A variety of inherited disorders result in compromise of the secretory or reabsorptive functions of the renal tubule system (Brenner and Rector, 1986). Prominent among them are defects in phosphate transport, amino acid transport, and glucose-handling. The clinical characteristics of people affected by these genetic defects of metabolism are, for the most part, well reviewed in standard medical texts, and inheritance patterns have also been well studied.

Affected persons with tubular impairment that does not reach clinical significance and those with late onset of disease might well be at increased risk for toxic injury. The issue deserves investigation.

Heredity also plays an important part in a wide variety of systemic diseases that can damage the kidney and thereby increase the risk of renal injury from biohazards. Among the most important are diabetes, hereditary amyloidosis, and alpha-antitrypsin deficiency (Brenner and Rector, 1986; Fisher and Brenner, 1989).

Autoimmune diseases, many kinds of vasculitis, and systemic lupus erythematosus can also be considered in this susceptibility category. Again, attention should be paid to family members of persons with diagnosed, clinically significant disease to identify the possible increased risk to apparently unaffected carriers of the defects.

Finally, hereditary aspects of immune responsiveness appear to contribute to the susceptibility to a number of renal diseases (Ballardie, 1992; Oliveira, 1992). That finding is not surprising in light of the great importance of immune and inflammatory responses in mechanisms of glomerular and tubulointerstitial disease. Long-term effects of toxic injury might involve immunopathologic mechanisms (see Chapter 4), and genetic aspects of immune responsiveness could contribute substantially to susceptibility to kidney damage from exposure to biohazards.

Susceptibility to develop Goodpasture's syndrome, with anti-glomerular-basement-membrane antibodies, appears to be strongly associated with a very small number of Class II major histocompatibility antigens; other Class II histocompatibility antigens have been implicated in susceptibility to membranous nephropathy (Oliveira, 1992). The link with immune response genes is of special importance in susceptibility to toxic injury, inasmuch as organic solvents, heavy metals, and drugs have also been suggested to play a role in the pathogenesis of those immune disorders of glomeruli (see Chapter 4). Class II major histocompatibility antigens have also been evaluated in the heredity of

IgA nephropathies, membranoproliferative glomerulonephritis, minimal change disease and tubulointerstitial nephritis (Oliveira, 1992). Although some claim to have established significant associations, the results remain controversial, requiring study of larger populations and more investigation. Evidence has suggested a role of genes of Class I major histocompatibility antigens in susceptibility to injury by immunological mechanisms. At present, however, it seems that linkage-disequilibrium phenomena can explain the link to Class I antigens, given the strong association with Class II antigens of the histocompatibility complex. Genetic deficiencies of the complement system, many of them also mapping in the major histocompatibility complex, have been shown to be predisposing factors in lupus nephritis and IgA nephropathy. Studies with animal models have identified highly significant genetic components of susceptibility to experimental tubulointerstitial nephropathies, but little or no similar evidence is available on humans (Ballardie, 1992).

Nutrition

The glomerular hyperfiltration that regularly follows the ingestion of a protein-rich diet can induce glomerulosclerosis and chronic renal failure in animals deprived of their renal reserve. Furthermore, variation in the body's mineral content has been linked with chronic renal injury, as in the case of severe hypokalemia induced by eating disorders, and shown to augment toxicant-caused injury, as in the association of calcium depletion with lead nephropathy or of salt depletion with analgesic nephropathy.

Socioeconomic Factors

The relationship between income and the incidence of ESRD has previously been described (see Chapter 2).

It is not clear whether income is a true independent variable or is closely associated with race or other factors.

Age

Age is a well-recognized factor in determining the severity of acute renal failure—particularly that acquired in hospitalized patients (Porter, 1989). In older patients, not only is there an increased susceptibility to injury, but once injury has occurred the rate of recovery is decreased. For example, weanling rats, as opposed to adult rats, are relatively resistant to the nephrotoxic effects of aminoglycoside antibiotics and have a greater capacity for tubular epithelial-cell repair (Fernandez-Repollet et al., 1992).

There is indirect support of the proposition that the elderly are at increased risk for the development of toxicant-induced chronic renal failure. In a study of patients who were 70 years old or older (Chester et al., 1979), 29% of the

patients were classified as having chronic interstitial nephritis, a diagnosis quite compatible with toxicant- induced renal failure. The proportion was much higher than the 10.4%, observed when patients 50 and older were included (Marcias-Nunez and Cameron, 1987). Because toxicant-induced chronic renal failure is theorized to occur after years of low-level exposure, it stands to reason that the incidence of chronic renal failure would be clustered in elderly patients.

Coexisting Chronic Disease

Pre-existing renal insufficiency is well documented as a risk factor in acute nephrotoxic renal failure. For chronic renal failure, the information is circumstantial. Patients with sickle-cell disease who have a high incidence of renal papillary necrosis as a result of their underlying disease process also have a predisposition to analgesic use because of the pain associated with "sickle crisis." In this situation, it is difficult to determine whether the analgesic use increases the severity of the papillary necrosis. Another example of the relationship between pre-existing renal insufficiency and acute nephrotoxic renal failure is the increased risk of nephropathy associated with contrast medium in patients with diabetes mellitus or multiple myeloma. It has been suggested (Mudge, 1980) that in up to 25% of diabetic patients with contrast-medium-induced renal injury, the serum creatinine concentration does not return to baseline, and further deterioration of renal function occurs. The role of hypertension was alluded to in the discussion of race. Presence or absence of coexisting chronic disease in other organs can modify the effects of some urinary tract toxicants.

Addictive Behavior and Recreational Drug Use

Drug abuse is increasingly common among young people, and it is not surprising that it has been linked to renal injury. Heroin use is associated with a severe form of nephropathy and is a recognized cause of focal sclerosing glomerulonephritis with associated nephrotic syndrome. The resulting glomerular injury often progresses to ESRD and might account for up to 10% of the cases of ESRD in cities with large addicted populations (Cunningham et al., 1983). Renal ischemia can be an acute effect of cocaine inhalations, although cardiac ischemia and cerebral ischemia are more common (Pogue and Nurse, 1989; Singhal et al., 1990).

Rhabdomyolysis and acute renal failure can accompany free-basing inhalation of cocaine (Horst et al., 1991).

Various acid-base and electrolyte abnormalities can result from solvent abuse, as occurs with exposure to toluene from gluesniffing (Carlisle et al., 1991; Gupta et al., 1991). When intravenous amphetamine (speed) was a popular street drug, a form of drug-induced polyarteritis nodosa

with progressive renal failure and severe hypertension was a recognized outcome.

Occupational or Environmental Exposure

Drugs and environmental toxicants have in some instances induced acute renal failure but evidence of their causing the development or progression of chronic renal failure is circumstantial and thus less compelling. That is not surprising, given the insidious and progressive nature of chronic renal failure and the long latency between exposure and the onset of disease. Compounding this is the superimposition of other chronic conditions that are also associated with progressive renal failure and the lack of a uniform system of classifying renal disease.

Finally, the presence of many potential nephrotoxicants in our environment suggests that the causes of many forms of renal failure are multifactorial (Sandler, 1987).

It has been estimated that nearly 4 million workers were exposed to known or suspected nephrotoxicants in the workplace in 1971–1972 (Landrigan et al., 1984). It is of interest to note that the specific nephrotoxicants that were cited in preparing that estimate are those believed to be capable of producing chronic renal failure and eventually ESRD. They include heavy metals (e.g., lead, mercury, uranium, and cadmium), solvents (especially light hydrocarbons), silica, beryllium, pesticides, and arsenic.

Solvents have been implicated as inducers of glomerulonephritis (Sandier and Smith, 1991), and the association between chronic interstitial nephritis and analgesic abuse is widely recognized (Gregg et al., 1989).

The association between hypertensive renal disease (nephrosclerosis) and lead nephropathy continues to be explored (Staessen et al., 1990). In evaluating the occurrence of lead nephropathy in the general public, Staessen et al. (1992) concluded that although lead exposure could impair renal function, they were unable to demonstrate a cause-effect relationship. Examples of environmental contamination that have renal consequences are many.

One that stands out is the poisoning by methyl mercury in industrial effluents that occurred in the Minamata Bay region of Japan and resulted in neurologic and renal impairment in several hundred adults who ate tainted fish (Iesato et al., 1977).

Table 3-1 provides a breakdown of some common chemical agents that cause nephrotoxicity.

MARKERS OF SUSCEPTIBILITY

One of the most important factors in the development of a xenobiotic-induced disease process is susceptibility. It would be of great advantage to be able to predict an individual's susceptibility to the adverse effects of a xenobiotic. Given the broad definition of biologic markers in general as indicators of variations in cellular or physiologic components or processes that alter structure or function, it is reasonable to

TABLE 3-1 Common Chemical Agents That Cause Nephrotoxicity Industrial and Environmental Substances

• Glycols

• Heavy metals

• Organic solvents

• Insecticides, herbicides, fungicides Drugs

• Prescription Antibiotics Antibacterial agents Antiviral agents Antifungal agents Immunosuppressive agents Antineoplastic agents

• Nonprescription, including nonsteroidal anti-inflammatory drugs

• Illicit (recreational), including heroin and cocaine

extend the definition to include genotypic (reflecting genetic constitution of the individual) or phenotypic (reflecting the entire' physical, biochemical, and physiologic makeup of an individual as determined both genetically and environmentally) markers as indicators of susceptibility. Genetic changes can result from exogenous exposures to occupational or environmental toxicants. These changes or mutations in DNA are usually considered markers of effect but under some circumstances can serve as markers of susceptibility.

The objective of this section is to provide a framework for identifying markers of susceptibility and determining their relative value for individual risk assessment. Ideally, the relationship between the presence of the marker and the incidence of disease has high degrees of sensitivity and specificity (see Chapter 1). If that is not the case, many people with a given marker of susceptibility might be monitored unnecessarily.

It is reasonable to use the techniques of molecular biology to identify new or more precise markers of susceptibility. Care must be taken to distinguish between the effects of acute high-level exposure and chronic low-level exposure. For example, in two separate population studies of the relationship of exposure to aromatic amines and the development of bladder cancer, outcome could not be predicted on the basis of the industrial- hygiene guidelines for estimates of peak exposure, but outcome and duration of exposure were statistically correlated. Epidemiologic studies are useful for identifying xenobiotic substances with overt health effects and to set standards for exposure, but it might be difficult to determine the percentage of people who suffer adverse health effects of low-level exposure or of exposures to multiple agents in population studies. The interaction of multiple low-level toxicants might be difficult to elucidate even in a multivariate analysis.

Modifying Factors of Susceptibility

In assessing potential risk, it is important in any model to account for individual variability of drug- metabolizing

Dalam dokumen Free Executive Summary (Halaman 66-94)