The liver is highly sensitive to effects of numerous organic and inorganic substances used in the workplace [see Table 1 ]. Despite the impressive potential for harm, often at exposure levels not uncommon in the workplace, occupational liver diseases are rarely recognized except during outbreaks.49 This is almost certainly because the clinical presentation is nonspecific, most often consisting of unsuspected elevations of hepatocellular enzymes occasionally associated with mild gastrointestinal symptoms. The single exception to this is the now extremely rare vascular disorder resembling veno-occlusive disease that is caused by vinyl chloride.
The more common hepatic effects of occupational hazards— steatosis and nonspecific hepatocellular injury—have numerous causes and are prevalent in the general population; a given case may be readily attributed to infection, alcohol use, drug toxicity, biliary tract disease, diabetes, obesity, or weight change. When persistent elevations of hepatic enzymes prompt more extensive workup with radiographic studies and biopsy, results rarely provide specific evidence of an occupational cause. Only high suspicion of a workplace culprit, combined with evidence of exposure to a suspect agent, serves to distinguish etiology.
Central and peripheral nervous systems
Most pesticides,50 organic solvents,51 and many metals52 are neurotoxic at doses that may be seen in the workplace [see Table 1]. A handful of other chemicals used in plastics, lubricating fluids, and chemical operations are also neurotoxic; most cases occur after accidental or unusual exposures. In addition, persons exposed to asphyxiants, such as carbon monoxide and cyanide, may present with acute or recurring central nervous system symptoms. Both acute and late effects may occur—the former typically occurring immediately after an intense exposure, the latter often after prolonged periods of exposure. Importantly, the late or chronic effects usually result from prolonged periods of bioaccumulation or recurrent mild or subclinical acute exposures or as sequelae of acute intoxication. A direct consequence of this toxicologic fact is that neurotoxicity almost invariably presents during the time of occupational exposure to the offending agent and not long afterward, as may occur with carcinogenic substances or dusts causing pneumoconiosis.
Because of the extraordinarily diverse range of clinical symptoms that may herald CNS toxicity, including subtle changes in cognitive and affective function, the evaluation of suspected cases follows the general principles for all occupational disease, with increased attention given to recent exposures. The acute disorders usually occur as mild alterations of CNS function,53 often with associated GI or other systemic effects; they are often recurrent, cycling with periods of work exposure, as might be seen in a painter (through exposure to solvents) or a pest-control worker. The key to recognition is the temporal pattern, with remission of symptoms occurring over a course of time consistent with the metabolism of the toxin. There may also be evidence of symptoms associated with withdrawal, similar to the effects associated with ethyl alcohol. For the subacute and chronic effects, the key to diagnosis is identification of evidence of substantial exposure occurring over a course of time consistent with the evolving neurotoxic picture. None of the neurologic disorders appear to involve allergy or idiosyncrasy; thus, the doses of exposure involved must be substantive.
In many cases, the exposure to the agent can be biologically confirmed with measurement of the levels of metal in the urine or blood, measurement of cholinesterase levels, or identification of a metabolite of an organic chemical in urine. There may also be some clinical or pathophysiologic clues. For example, the constellation of cerebellar ataxia, personality change, and salivary gland hypersecretion should prompt consideration of inorganic mercurialism, possibly with associated renal effects. An asymmetrical motor neuropathy should always raise the specter of lead poisoning. Insidious symmetrical distal sensory neuropathies, on the other hand, are far more common with solvents and acrylamide; electrophysiologic or pathologic evaluation reveals almost pure axonal degeneration, with minimal secondary de-myelination—an important differential feature. Highly localized neuropathies, either unilateral or bilateral, should raise the possibility of a compressive etiology, not uncommon with repetitive work activities [see Musculoskeletal Disorders, below].54
Although diagnosis may be straightforward once the possibility of a workplace agent is considered, management remains challenging. Treatment of acute disorders involves ending the exposure and providing support where clinically necessary. Several hazards, such as certain cholinesterase inhibitors and cyanide, have specific antidotes that should be administered under medical supervision. The subacute and chronic conditions all require removal from further exposure. In addition, patients with heavy-metal exposure may be given chelation therapy when signs and symptoms of severe intoxication are evident; this, too, must be done under very close supervision in view of the risk of enhancing CNS effects early in treatment. Moreover, the possibility of rebound effects from reequilibration of metal into the nervous system must be anticipated when chelation is stopped. Most important, whatever strategy is chosen, physician and patient must be aware that the prognosis for full recovery from all but the most acute effects is somewhat guarded. Axons regrow very slowly, and higher integrative functions, such as affective or cognitive functions of the CNS, resolve even more slowly or not completely. Early efforts at functional rehabilitation, as may be used for trauma or stroke patients, are indicated when impairments limit work or other major life activities.
Possibly the most challenging diagnostic situation in occupational neurology is the worker who presents with CNS-related complaints that exhibit a temporal pattern consistent with a workplace origin but who does not have substantial exposure to neu-rotoxic agents. Such symptoms are a common part of the so-called sick-building syndrome, now referred to as nonspecific building-related illness, and are universal among persons who have acquired intolerance to low levels of chemicals (multiple chemical sensitivities).55 It is important to recognize early that these syndromes are different from the neurotoxic disorders discussed here with regard to evaluation, prognosis, and treatment. They are discussed more fully later in this topic [see Clinical Problems Associated with Low-Level Environmental Exposures, below].
There has been a marked increase in the awareness of the role that work factors play in musculoskeletal disorders, ranging from such well-defined clinical problems as arthropathies and nerve compression syndromes to the less well characterized ailments causing pain of the trunk and extremities.54,56 In developed countries, such disorders account for billions of dollars of costs in medical care and lost productivity. The overwhelming bulk of this epidemic relates to suspected consequences of physical stressors and trauma that occur at work. A number of systemic occupational disorders may also have expression in the muscles, bones, joints, and connective tissues; important examples of such disorders are the arthralgias and gouty consequences of lead intoxication, bony pain in association with systemic fluorosis, and the apparent increased risk of scleroderma in miners.
It is clinically useful to divide potential occupational muscu-loskeletal disorders into those that have a well-defined anatomic structure of involvement, such as carpal tunnel syndrome, and those that lack such a clear-cut pattern, such as low back pain.58,59 Although extensive data suggest that physical aspects of work, such as overall force, repetition, awkward posture, and vibration, contribute in a cumulative fashion to the development of both localizable and nonspecific symptoms, the approach to diagnosis and treatment is somewhat different for each. There is also evidence that factors other than physical strain, such as work stress, work fatigue, and adverse relationships in the workplace, may be important contributory factors, partially explaining high rates of musculoskeletal disorders among certain white-collar workers.
For disorders of new onset involving the trunk or extremities or for clinically mild disorders, the initial approach should be short-term palliation with minimal workup. Rest from physically demanding tasks, use of nonsteroidal anti-inflammatory drugs or other nonnarcotic pain relievers, reassurance, and follow-up after a few days of treatment are suggested; further evaluation is indicated only if suggested by physical findings. If conservative steps fail to alleviate symptoms rapidly, additional examination and laboratory evaluation may be appropriate to rule out an anatomically discrete lesion that could be amenable to treatment. Where specific lesions are identified, such as compression of a nerve or disk or tenosynovial inflammation, longer-term efforts at elimination of strain in the affected region combined with anti-inflammatory drugs or other therapies are appropriate, followed by surgical intervention should these fail. In such cases, it is crucial to remember that the work-related stressors that caused the problem will complicate recovery unless they are modified.
The most perplexing problem is the management of patients whose complaints cannot be specifically localized by physical examination or, when necessary, electrophysiologic or radiolog-ic evaluation. Such complaints are no less real than those that are more readily understood and treated. Modification of work activities is often necessary but is rarely sufficient to resolve the problem. Pain may be persistent and refractory to treatment, and the value of physical therapy or pain medications is questionable. Rather, it is important for the treating physician to establish early that the symptoms are troublesome but not the result of a progressive process and that the patient may have to adapt to them despite discomfort. Expectation of cure often leads to unnecessary treatment, prolonged (and clinically unhelpful) loss of work time, and, ultimately, frustration on the part of the employer, the insurance company, the patient, and the physician.
A host of disturbances of red cell function, survival, and production have been attributed to workplace exposures, including acute, subacute, and chronic processes [see Table 1]. Effects involving other cell lines have seldom been reported and will not be discussed. In clinical practice, the biggest concerns are the risk of acute hemolysis in workers exposed to nitrogen-containing oxidant chemicals in pharmaceutical, chemical, and explosives manufacturing; the effects of lead, which remains ubiquitous in the work environment; and the potential for solvent-induced marrow injury. The problem of oxidant stressors is somewhat difficult. Although workers with marked deficiency of glucose-6-phosphate dehydrogenase (G6PD) should probably avoid significant contact with such chemicals, there is not a clear relation between any of the measurable enzyme levels and risk. It is prudent to periodically screen all exposed workers for subclinical evidence of hemolysis, as well as for subclinical accumulation of methemoglobin, which is often induced by the same agents; workers who show evidence of early effects should probably be removed from harm’s way, irrespective of identifiable factors.
The hematologic effects of lead are widely misunderstood.66,67 Although there is a dose-related inhibition of heme synthetase by lead that can be readily quantified by determining the accumulation of the precursor protoporphyrin (usually measured as whole blood zinc protoporphyrin), this biochemical effect of lead on blood hemoglobin or hematocrit is minimal until very high levels are reached, and there is almost no impact on red cell volume. In other words, anemia associated with hypoproliferation of red cells is very rare, and the absence of anemia should never be used to exclude a role for lead in causing toxicity to organs and systems that are far more sensitive, such as the nervous system and renal tubules. Furthermore, microcytosis can only occasionally be attributed to lead alone; when it is seen, especially in children, it most often signifies coincident iron deficiency. On the other hand, rapid accumulation of lead in acute lead poisoning, typically heralded clinically by the onset of abdominal pain, is almost always associated with evidence of rapid hemolysis; reticu-locyte counts are in the range of 5% to 20%. In this setting, the notorious basophilic stipples are frequently seen as well, though they are by no means pathognomonic for lead toxicity. In general, this syndrome will occur only after lead levels have exceeded 60 mg/dl in whole blood. The hemolysis tends to abruptly stop after effective chelation therapy, which is usually indicated in this acute symptomatic form of lead poisoning.
The bone marrow effects of workplace chemicals are only slowly being unraveled, but certain conclusions seem warranted. Benzene, the aromatic constituent of petroleum products, was once widely prevalent in the work environment as a solvent and a component of gasoline. It can cause hypoplastic injury to the marrow, which may directly progress to a chronic blood dyscrasia (i.e., myelodysplasia or leukemia), or dyscrasia may occur after apparent recovery.68 In other words, an exposed worker may show depressed cell counts, be removed from the source of toxicity, improve, and years later (possibly long after exposure ceases) develop myelodysplasia or a myeloprolifera-tive syndrome. It is likely that some workers will develop the obviously more serious dyscrasias without direct marrow injury having been recognized while exposure was ongoing. There are no hallmark features of either the hypoplastic state (occurring during ongoing exposure) or the myelodysplastic state (occurring later) that distinguish benzene toxicity from other causes of such disorders; this differentiation depends on the history of substantial benzene exposure, because the disorders are not believed to be idiosyncratic but dose related. Although there is some evidence that a few other solvents, such as the glycol ethers that are widely used in paints and coatings,69 may cause such injury, the vast majority of solvents, including many benzene congeners such as toluene and xylene, do not appear to have potential for marrow injury. For this reason, most products that formerly contained benzene that are used in developed countries have been modified, and benzene is not used directly except for specific purposes in the manufacture of chemicals and pharmaceuticals. Obviously, exposed persons should be carefully monitored for hematologic effects, the presence of which would be clear evidence of overexposure.
Endocrine and reproductive effects
Despite an exceptional upsurge in interest in the endocrine-disrupting effects of environmental contaminants, there is little evidence that occupational exposures to chemical hazards cause clinically relevant endocrinopathies in adults.70 Lead has been shown to impair hypothalamic-pituitary axis secretions and probably testosterone regulation in men heavily exposed, but the clinical relevance of these observations is unclear. Several compounds used in the pharmaceutical industry and other industries have been shown to have estrogenic activity, with predictable clinical consequences in both men and women.
The effects of work on male and female reproduction are a more formidable concern.71 Although data are far from complete because many chemicals have never been studied adequately, several substances at occupational levels of exposure have been proved to cause infertility and decreases in sperm counts; such substances include lead, the pesticides 1,2-dibro-mo-3-chloropropane (DBCP) and ethylene dibromide (EDB), ethylene glycol ethers, and carbon disulfide. Heat and ionizing radiation have also been associated with infertility and decreased sperm counts. In addition, a host of other metals, anesthetic agents, and plastic reagents have been shown to cause worrisome gonadal effects in toxicologic experiments on male animals. For this reason, infertile men should be carefully questioned about work exposures; they should be observed for signs of improvement for about 9 months (which equals four cycles of spermatogenesis) should suspicion of an occupational cause be entertained.
Female reproduction is harder to study for lack of a single body fluid to analyze and because of the absence of a simple animal model. There is evidence that several common exposures, including waste anesthetic gases, lead, glycol ethers, eth-ylene oxide, and antineoplastic drugs, have the potential to increase the risk of miscarriage. Lead, organic mercury, polychlo-rinated biphenyls (PCBs), heat, and ionizing radiation are established teratogens; organic solvents are also suspect on the basis of animal studies and new epidemiologic reports.72 Most of the agents that cause human cancer [see Table 3] are considered likely fetal hazards as well. In most cases, there is risk of adverse effects at doses considered acceptable in the workplace, because regulations have not traditionally been developed on the basis of reproductive concern. To a disturbing degree, knowledge of the reproductive effects of thousands of additional chemicals is unknown. Even the effects of hard physical work during pregnancy remain unclear, though there is evidence that excessive lifting and standing late in the third trimester may induce prematurity.
With the majority of women of reproductive age now in the workforce, many are questioning the safety of work during pregnancy, and clinicians are being confronted with trade-offs between fetal risks and the worker’s economic security. Although each case must be studied individually, a reasonable guideline is to rigorously protect patients from the established teratogens or ensure the levels of exposure below those established for pregnancy. For others, reasonable steps can be taken to minimize exposure, including job transfer if the patient prefers and the employer has alternative work. For the patient for whom any risk represents an unacceptable psychological impediment, transfer or removal is probably in the best interest of all parties.
Clinical problems associated with low-level environmental exposures
One of the most common problems emerging in developed countries is the constellation of respiratory and systemic complaints that are appearing with increasing frequency in office workers and others in what are traditionally considered safe jobs.73,74 Typical symptoms of sick-building syndrome, or nonspecific building-related illness, include upper and lower respiratory symptoms, often combined with neurologic problems, such as fatigue, headache, and cognitive deficits, as well as rashes and other nonspecific complaints.74 Usually, the patient will relate that others in the environment are experiencing similar difficulties and that the symptoms improve when the patient is away from work and return upon reexposure. Although in a minority of cases, investigation may reveal a specific allergy (e.g., in patients with asthma, rhinitis, or allergic alveolitis) or a specific hazard (e.g., fibrous glass released during a renovation or from a ventilation duct, causing pruritus), in the majority of cases, the environment is usually best described as poorly ventilated.74,75 At present, there is no specific treatment of this syndrome other than palliative care and reassurance that it is neither progressive nor life threatening.76,77 Expensive testing of either the patient or the work environment is rarely necessary or beneficial.74 Ideally, remediation of both should be undertaken as soon as more dire possibilities are excluded by history and a walk-through of the workplace by an industrial hygienist or comparable environmental professional. In the vast majority of cases, improvement of ventilation will result in symptomatic improvement for most workers.
On occasion, a patient in an affected building will start to experience similar discomfort in other situations, such as driving behind a bus, being in a store, or using a perfume or detergent.55 The net impression is that the patient has become reactive to everything that has an odor. Many also have fatigue or other as-thenic symptoms between exposures. Symptoms reminiscent of those in panic disorder may also occur. Dubbed multiple chemical sensitivities (MCS), this disorder is not associated with measurable abnormalities of organ system function but may be highly disabling.55 Although there are many physical and psychological theories regarding the origin of MCS, present knowledge is limited. Patients do not easily tolerate pharmacologic agents and usually do not respond to treatment for anxiety or depression. Avoidance is equally fruitless, with shorter and more trivial exposures causing problems in those who quit work and minimize human contact. At present, the recommended treatment is supportive care coupled with moderate life modifications to avoid the most provocative exposures while preserving everyday functioning, including work if possible. Unrealistic expectations of cure or remission are as harmful as unwarranted fears of deterioration; neither outcome appears common among patients followed for many years.